Osteoporosis is increasingly reported in the aging HIV-positive population, and co-infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV-related increased fracture risk is a function of the severity of liver disease. We calculated the time-updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV-infected patients enrolled in the Veterans Affairs' Clinical Case Registry between 1984 and 2009. The association between HCV co-infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV-infected patients (98.1% male; 31.3% HCV co-infected; median age 44.0 years) contributing 305,237 patient-years of follow-up. Fracture rates were significantly higher among HIV/HCV patients than HIV-only patients (2.57 versus 2.07/1000 patient-years, relative risk = 1.24, p < 0.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co-infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR] = 1.32; p < 0.001) or APRI score (HR = 1.30; p = 0.003). Among HIV/HCV co-infected patients, cirrhosis strongly predicted osteoporotic fractures (HR = 1.65; 95% confidence interval [CI] 1.11–2.44; p = 0.012), but APRI score was a weaker predictor (HR = 1.008; 95% CI 1.002–1.014; p = 0.015). In conclusion, among HIV-infected patients, severity of liver disease partly explains the HCV-associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined. © 2013 American Society for Bone and Mineral Research.