Background: Hospitalization events exact a substantial toll across the age spectrum. Frailty is associated with all-cause hospitalization among HIV-uninfected adults aged 65 years and older. Limited data exist on the frailty relationship to hospitalization among HIV-infected persons or those aged less than 65 years. Comparative investigation of the frailty relationship to specific classes of hospitalizations has rarely been reported among adults of any age. This study sought to determine the frailty relationship to three distinct classes of hospitalization events among HIV-infected persons and their uninfected counterparts. Methods: Frailty was ascertained semiannually among persons with prior injection drug use using the five Fried phenotypic domains. Hospitalization events were categorized using Agency for Healthcare Research and Quality clinical classification software into chronic, infectious, and nonchronic, noninfectious conditions. Cox proportional hazards models were used to examine the frailty relationship to time to first hospitalization event. Results: Among 1,303 subjects, mean age was 48 years; 32% were HIV-infected. Adjusting for sociodemographics, comorbidity, substance use, and HIV disease stage, time-updated frailty status was associated with risk for all hospitalization classes. Baseline frailty was significantly associated with all-cause (hazards ratio [HR] 1.41; 95% confidence interval [CI], 1.06, 1.87), chronic (HR 2.13; 95% CI, 1.46, 3.11), and infectious disease hospitalization (HR 2.51; 95% CI, 1.60, 3.91) but not with nonchronic, noninfectious hospitalization risk (HR 1.09; 95% CI, 0.74, 1.61). Conclusion: The frailty phenotype predicts vulnerability to chronic and infectious disease-related hospitalization. Frailty-targeted interventions may mitigate the substantial burden of infectious and chronic disease-related morbidity and health care utilization in HIV-infected and uninfected populations.