Narcotic analgesics are commonly prescribed drugs in patients with chronic hepatitis C (CHC) infection. In vitro data have shown that morphine enhances hepatitis C virus replication in human hepatic cells, however the effect of narcotics on hepatitis C virus disease progression remains uncertain. The aim of this study was to evaluate the potential effects of narcotic analgesic use on the progression of hepatic fibrosis in patients with CHC infection. We identified CHC patients who had been seen at our institution and had undergone a liver biopsy between 1990 and 2005. Their charts were reviewed for the presence of narcotic analgesic and known risk factors for progression of hepatic fibrosis including male sex, age > or =40, obesity, diabetes, and alcohol abuse. All biopsy were reviewed and fibrosis scores were standardized using the Batts and Ludwig scoring system (stage 0 to 4). A total of 1147 evaluable patients were identified and 171 of these had narcotic analgesic use. In univariate analysis, narcotic analgesic use was associated with the presence of alcohol abuse (P<0.001), obesity (P=0.02), and advanced fibrosis defined as stage 3 to 4 fibrosis (P=0.02), but not with male sex or diabetes. In multivariate logistic regression analysis, obesity [odds ratio (OR) 1.68 (confidence interval (CI), 1.21-2.33)], alcohol abuse [OR 1.45 (CI, 1.04-2.02)], age > or =40 [OR 1.85 (CI, 1.22-2.89)], and diabetes [OR 2.43 (CI, 1.41-4.14)] all independently predicted advanced liver fibrosis but narcotic analgesic use did not [OR 1.71 (CI, 0.99-2.89)]. As the amount of narcotic analgesic use increased from no use, to <3 months use, to > or =3 months use, the frequency of obesity, alcohol abuse, and advanced fibrosis increased accordingly (P=0.005), suggesting that it is difficult to separate these known risk factors from narcotic use as the cause for advanced fibrosis in this population.