OBJECTIVE To define the contributions of human immunodeficiency virus (HIV) and hepatitis C virus infections to the development of porphyria cutanea tarda. METHODS Analysis of serum porphyrin levels in a cohort of 167 subjects. Serum samples were divided into 4 groups corresponding to the status of HIV and hepatitis C virus infections: positive-positive, positive-negative, negative-positive, and negative-negative. METHODS Serum samples positive for HIV were obtained from the serum bank of an acquired immunodeficiency syndrome-HIV research center, and HIV-negative samples were obtained from a regional blood center. METHODS Spectrofluorometric measurement of serum porphyrin levels. RESULTS The median values of porphyrin were 2.31 nmol/L (interquartile range [difference between the 25th and 75th percentiles]: 4.55) in the positive-positive group, 1.99 nmol/L (interquartile range: 1.63) in the positive-negative group, 1.31 nmol/L (interquartile range: 1.58) in the negative-positive group, and 1.14 nmol/L (interquartile range: 0.92) in the negative-negative group. The fluorescence emission spectra of samples with elevated porphyrin levels were identical with that reported for porphyria cutanea tarda. Elevated porphyrin levels were significantly associated with HIV infection (P < .001) and were observed in patients with an elevated level of alanine aminotransferase (P = .03). Infection with hepatitis C virus was also associated with an elevation in porphyrin levels, although the increase was not statistically significant (P = .16). Porphyrin levels in patients positive for HIV were not correlated with serum urea nitrogen or creatinine levels. None of the patients had symptomatic porphyria cutanea tarda. CONCLUSIONS Factors associated with increased serum porphyrin levels included HIV infection, elevated alanine aminotransferase levels, and, to a lesser extent, hepatitis C virus infection. These findings suggest that patients with the above risk factors are potentially predisposed to the development of symptomatic porphyria cutanea tarda on further exposure to hepatotoxic agents.