Tattooing in commercial tattoo parlors is known to transmit blood-borne viral infections, including hepatitis C virus (HCV), in other countries, but its contribution to the high population prevalence of HCV infection in the United States has been incompletely evaluated. Risk factors for blood-borne infection were assessed by physician's interview of 626 consecutive patients undergoing medical evaluation for spinal problems in 1991 and 1992 while unaware of their HCV status. Later all were screened for HCV infection with enzyme-linked immunosorbent assay (EIA-1 and EIA-2), and positives were confirmed with second-generation recombinant immunoblot assay (RIBA). Forty-three patients were seropositive for HCV (sample prevalence 6.9%, population-standardized prevalence 2.8%). Logistic regression analysis identified 4 independent risk factors for HCV infection: injection-drug use (adjusted prevalence odds ratio [OR] = 23.0; 95% confidence intervals [CI] = 7.5-70.6), ancillary hospital jobs held by men (OR = 9.6; 95% CI = 3.8-24.3), tattoos from commercial tattoo parlors (OR = 6.5; 95% CI = 2.9-14.8), and drinking > or = 3 6-packs of beer per month (OR = 4.0; 95% CI = 1.8-8.7). If causal, these 4 risk factors account for 91% of HCV infections, with tattooing explaining 41%, heavy beer drinking 23%, injection-drug use 17%, and ancillary health care jobs for men 8%. Transfusions, promiscuous sexual activity, bone grafts, acupuncture, perinatal or intimate transmission in families, and other modes were not independently associated with serologic evidence of HCV infection. Unlikely to be explained by confounding or incomplete disclosure of other risk factors, tattooing in commercial tattoo parlors may have been responsible for more HCV infections than injection-drug use.