BACKGROUND: Medication classes, polypharmacy, and hazardous alcohol and illicit substance abuse may exhibit stronger associations with serious falls among persons living with HIV (PLWH) than with uninfected comparators. We investigated whether these associations differed by HIV status. SETTING: Veterans Aging Cohort Study. METHODS: We used a nested case-control design. Cases (N = 13,530) were those who fell. Falls were identified by external cause of injury codes and a machine-learning algorithm applied to radiology reports. Cases were matched to controls (N = 67,060) by age, race, sex, HIV status, duration of observation, and baseline date. Risk factors included medication classes, count of unique non-antiretroviral therapy (non-ART) medications, and hazardous alcohol and illicit substance use. We used unconditional logistic regression to evaluate associations. RESULTS: Among PLWH, benzodiazepines [odds ratio (OR) 1.24; 95% confidence interval (CI) 1.08 to 1.40] and muscle relaxants (OR 1.29; 95% CI: 1.08 to 1.46) were associated with serious falls but not among uninfected (P > 0.05). In both groups, key risk factors included non-ART medications (per 5 medications) (OR 1.20, 95% CI: 1.17 to 1.23), illicit substance use/abuse (OR 1.44; 95% CI: 1.34 to 1.55), hazardous alcohol use (OR 1.30; 95% CI: 1.23 to 1.37), and an opioid prescription (OR 1.35; 95% CI: 1.29 to 1.41). CONCLUSION: Benzodiazepines and muscle relaxants were associated with serious falls among PLWH. Non-ART medication count, hazardous alcohol and illicit substance use, and opioid prescriptions were associated with serious falls in both groups. Prevention of serious falls should focus on reducing specific classes and absolute number of medications and both alcohol and illicit substance use.