Abstract BACKGROUND: Older healthy and HIV-infected adults exhibit physiological similarities. Frailty is a clinical syndrome associated with aging that identifies a subset of older adults at high risk of mortality and other outcomes. We investigated whether HIV infection increases the prevalence of a frailty-related phenotype (FRP) that approximates a clinical definition of frailty. METHODS: We first defined the FRP and assessed its prevalence among HIV-uninfected men followed in the Multicenter AIDS Cohort Study (MACS) between 1994 and 2004. Using repeated measurements logistic regression models, we then assessed the association between FRP and HIV infection before the era of highly active antiretroviral therapies, adjusting for covariates among HIV-uninfected (N = 1905) and incident HIV cases (N = 245). RESULTS: HIV infection was strongly associated with FRP prevalence. Compared to HIV-uninfected men of similar age, ethnicity and education, HIV-infected men were more likely to have the FRP for all durations of infection: for < or =4 years, the adjusted odds ratio (OR) was 3.38, with 95% confidence interval (CI), 1.25-9.11, and for 4.01-8 years and 8.01-12 years the corresponding figures were (OR = 12.95, 95% CI, 6.60-25.40) and (OR = 14.68, 95% CI, 7.60-28.35), respectively. The FRP prevalence for 55-year-old men infected with HIV for < or =4 years (3.4%; 95% CI, 1.3-8.6) was similar to that of uninfected men > or =65 years old (3.4%; 95% CI, 1.5-7.6). CONCLUSION: In this cohort, HIV infection was associated with an earlier occurrence of a phenotype that resembles the phenotype of frailty in older adults without HIV infection. Studies of frailty in the setting of HIV infection may help to clarify the biological mechanism of frailty.