Introduction: The genetics of hereditary hemochromatosis (HH) is understudied in Iran. Here, we report the result of genetic screening of 854 individuals, referred as "suspected cases of HH," to a diagnostic laboratory in Iran over a 12-year period. Materials and Methods: From 2011 to 2012, 121 cases were screened for HH using Sanger sequencing of HFE exons. After 2012, this method was replaced by a commercial reverse hybridization assay (RHA) targeting 18 variants in the HFE, TFR2, and FPN1(SLC40A1) genes and 733 cases were screened using this method. Results: From the total studied population, HH was confirmed by genetic diagnosis in only seven cases (0.82%): two homozygotes for HFE:C282Y and five homozygotes for TFR2:AVAQ 594-597 deletion. In 254 cases (29.7%), H63D, C282Y, S65C, and four other HFE variants not targeted by RHA were identified. Although the resulting genotypes in the latter cases did not confirm HH, some of them were known modifying factors of iron overload or could cause HH in combination with a possibly undetected variant. No variant was detected in 593 cases (69.4%). Conclusion: This study showed that the spectrum of genetic variants of HH in the Iranian population includes HFE and TFR2 variants. However, HH was not confirmed in the majority (99.2%) of suspected cases. This could be explained by limitations of our genetic diagnostics and possible inaccuracies in clinical suspicion of HH. A cooperative clinical and genetic investigation is proposed as a solution to this issue. TFR2-related hemochromatosis (TFR2-HC) is characterized by increased intestinal iron absorption resulting in iron accumulation in the liver, heart, pancreas, and endocrine organs. Age of onset is earlier than in HFE-related hemochromatosis. The majority of individuals present with signs and symptoms of iron overload in the third decade (e.g., weakness, fatigue, abdominal pain, hepatomegaly, arthritis, arthralgia, and progressive increase in skin pigmentation). Others present as young adults with nonspecific symptoms and abnormal serum iron studies or as adults with abnormal serum iron studies and signs of organ involvement including cirrhosis, diabetes mellitus, arthropathy, hypogonadism, cardiomyopathy, and increase in skin pigmentation. The diagnosis of TFR2-HC is established in a proband with biallelic pathogenic variants in TFR2 identified by molecular genetic testing. Targeted therapy: In order to prevent iron overload-related complications, removal of excess iron by routine phlebotomy to maintain serum ferritin concentration at 50 ng/mL or lower and transferrin-iron saturation below 50%; iron chelation therapy as needed in those with anemia. Supportive care: Vaccination for hepatitis A and B; therapy to prevent cirrhosis complications and liver decompensation including endoscopic surveillance of varices and prophylaxis with nonselective beta-blockers; salt restriction and diuretics for ascites with paracentesis and shunts as needed; antibiotics for spontaneous bacterial peritonitis; low protein diet for hepatic encephalopathy with lactulose and rifaximin as needed; hormone replacement therapy for hypogonadism; gonadotropins for fertility/pregnancy; routine treatment for diabetes mellitus and cardiac failure; nonsteroidal anti-inflammatory drugs and joint replacement for arthropathy. Surveillance: Serum iron, transferrin, transferrin saturation, and ferritin concentration every six to 12 months once serum ferritin concentration is lower than 50 ng/mL. Serum AFP and liver ultrasound in individuals with cirrhosis every six months to assess for hepatic complications and for early detection of hepatocarcinoma. Individuals with hypogonadism, diabetes mellitus, and cardiac failure should have surveillance for complications related to the specific organ failure. Agents/circumstances to avoid: Medicinal iron and nutritional supplements containing iron, excessive alcohol intake, vitamin C supplements, uncooked seafood, and lifestyle-related behaviors that increase the risk of viral hepatitis infection. Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the TFR2 pathogenic variants found in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Pregnancy management: Phlebotomy can be paused in pregnant women with mild-to-moderate iron overload due to fetal utilization of maternal iron. TFR2-HC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TFR2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Once the TFR2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.