Background: Porphyria cutanea tarda (PCT) and hepatitis C virus (HCV) infection have been associated in several reports with the prevalence of HCV exhibiting considerable regional variation. However, most reports were confounded by selection bias and a regional prevalence of HCV in the populations studied. In the United States, only a few cases of this association have been reported to date. Objective: We conducted a study to evaluate the association between PCT and HCV in a US population. We used a case-control study design to control the systemic error that may occur during a selecting process or sampling procedure. Methods: We reviewed the medical records of Wishard Memorial Hospital, a county hospital serving metropolitan Indianapolis, Indiana, to perform a retrospective case-control study of 26 patients with PCT (as case) against 149,756 regional volunteer blood donors (as control-1) and 51 patients receiving methotrexate for psoriasis (as control-2). HCV antibody titers and other liver abnormalities were our main outcome measures. We then performed a weighted meta-analysis of 17 reports that had at least 17 patients in their study populations. Results: Sixteen (94%) of 17 PCT patients tested for HCV were antibody positive. Among blood donors, only 255 or 0.17% were HCV antibody positive ( P < 10-5, two-sided chi-square test). Of 5 psoriasis patients tested for HCV, none were HCV antibody positive ( P = .0002, two-sided Fisher’s exact test). For geographic comparison, meta-analysis of the literature demonstrated a varying regional prevalence of HCV in PCT patients as follows: Northern Europe 17%, Australia/New Zealand 20%, and Southern Europe 65%. Conclusion: Although a marked geographic variation was found in the worldwide prevalence of HCV in PCT patients, a very large percentage of US patients with PCT had HCV infection. Our results emphasize the need for clinicians to actively look for HCV in patients with PCT. (J Am Acad Dermatol 1999;41:31-6.)