Both HIV and hepatitis C virus (HCV) cause chronic inflammation and alterations in serum inflammatory cytokines. The impact of inflammatory cytokines on liver fibrosis is not well understood. We studied the association between interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α and liver fibrosis in HIV-infected patients with current or past alcohol problems (CAGE ≥2 or physician investigator diagnosis). Liver fibrosis was estimated with FIB-4 (FIB-4 <1.45 defined the absence of liver fibrosis and FIB-4 >3.25 defined advanced fibrosis). Logistic regression was used to assess the association between cytokines and fibrosis, adjusting for age, sex, CD4, HIV RNA, current antiretroviral therapy, body mass index, and HCV. Secondary analyses explored whether the association between HCV and liver fibrosis was mediated by these cytokines. Participants (n=308) were all HIV-infected; 73% were male with a mean age of 42 years; half had detectable HCV-RNA, 60.7% had an absence of liver fibrosis, and 10.1% had advanced fibrosis. In models that adjusted for each cytokine separately, higher levels of IL-6 were significantly associated with an absence of fibrosis [adjusted OR (95% CI): 0.43 (0.19, 0.98), p=0.05] and were borderline significant for advanced fibrosis [adjusted OR (95% CI): 8.16 (0.96, 69.54), p=0.055]. In the final model, only higher levels of IL-6 remained significantly associated with advanced liver fibrosis [adjusted OR (95% CI): 11.78 (1.17, 118.19), p=0.036]. Adjustment for inflammatory cytokines attenuated the adjusted OR for the association between HCV and fibrosis in the case of IL-6 [for the absence of fibrosis from 0.32 (0.17, 0.57) p<0.01 to 0.47 (0.23, 0.96) p=0.04; and for advanced fibrosis from 7.22 (2.01, 25.96) p<0.01 to 6.62 (1.20, 36.62) p=0.03], suggesting IL-6 may be a partial mediator of the association between HCV and liver fibrosis. IL-6 was strongly and significantly associated with liver fibrosis in a cohort of HIV-infected patients with alcohol problems. IL-6 may be a useful predictive marker for liver fibrosis for HIV-infected patients.