Background Both HIV infection and frailty have been associated with chronic immune activation. One possible explanation for this chronic immune activation could be low levels of CD4(+) T regulatory cells (Tregs), which suppress immune responses. Methods HIV-uninfected (HIV-) and HIV-infected (HIV+) men in the Multicenter AIDS Cohort Study (MACS) were classified as frail (or nonfrail) if they expressed (or did not express) the Fried frailty phenotype at two consecutive study visits. Percentages and absolute numbers of total Tregs, and percentages of different subsets of Tregs and of activated T cells were measured by flow cytometry. The function of Tregs was measured by suppression of T-cell proliferation. Results Percentages of Tregs were higher, rather than lower, in frail men than in nonfrail men, and this difference was significant for HIV- men. Percentages of subsets of Tregs did not differ significantly by frailty status. Among HIV+ men, the suppressive function of Tregs was similar between frail and nonfrail men. Percentages of Tregs and activated T cells were negatively correlated in nonfrail men (HIV- and HIV+) and in frail HIV- men, but this correlation was strongly positive in frail HIV+ men. Conclusion These data suggest that: (a) Tregs were not deficient in frail men; and (b) the immunological pathophysiology of frailty may differ by HIV status.