HIV and methamphetamine (MA) use disorder are commonly comorbid and individually associated with adverse health consequences, including frailty; however, less is known about the combined effects of both conditions. The current cross-sectional study examined how HIV and lifetime MA use disorder relate to frailty and explored associations between frailty and relevant clinical outcomes (i.e., neurocognitive and everyday functioning). Participants were categorized into three groups based on HIV status and lifetime MA diagnosis: HIV+/MA+ ( n = 43), HIV+/MA− ( n = 75), and HIV−/MA− ( n = 92). A frailty index score (representing proportion of accumulated multisystem deficits) was calculated from 27 medical and psychiatric deficits. Multiple regression was used to examine frailty index score by HIV/MA group. Additional multiple regression models examined the interaction between frailty and HIV/MA group on cognitive and everyday functioning. Comorbid HIV+/MA+ participants had higher frailty index scores than both HIV−/MA− ( b = −0.13, p < .001) and HIV+/MA− participants ( b = −0.06, p = .007). Additional models linked higher frailty index score to worse global neurocognition ( b = −17.6, p = .018) and greater likelihood of everyday functioning dependence (odds ratio = 1.56, p = .021). Although these relationships did not significantly differ by HIV/MA status, group-stratified analyses showed that associations of frailty with neurocognitive and everyday functioning were strongest among the HIV+/MA+ group. Multimodal public health interventions aimed at reducing frailty may help to decrease the likelihood of neurocognitive and everyday functioning problems. Current findings additionally lay groundwork for future longitudinal research examining whether frailty predicts onset of neurocognitive and functional decline in individuals with comorbid HIV and MA use disorder.