Abstract Background Severe bacterial infections are the first cause of morbidity in people with human immunodeficiency virus (PWH). We aimed to assess their incidence and to analyze their determinants. Methods We studied human immunodeficiency virus (HIV)-1-infected individuals aged at least 15 years and prospectively followed between 2006 and 2015 in the French Hospital Database on HIV. The Andersen and Gill model was used to calculate the adjusted hazard ratios (HRs), focusing on heavy alcohol use and neutrophil function-altering comorbidities. Results Of 25 795 participants, 1414 developed 1883 severe bacterial infections. Between 2006 and 2009 and 2013 and 2015, the incidence fell from 13.2 (95% confidence interval [CI], 12.3–14.1) to 7.1 (95% CI, 6.3–7.8) per 1000 person-years. Heavy alcohol use was associated with an increased risk of severe bacterial infection (HR = 1.3, 95% CI = 1.1–1.7 for 40–80 g/day and HR = 1.6, 95% CI = 1.2–2.1 for >80 g/day), as were diabetes, chronic kidney disease, and end-stage liver disease (HR = 1.2, 95% CI = 1.0–1.4 when 1 comorbidity; HR = 2.3, 95% CI = 1.6–3.4 when more than 1 comorbidity), and nonacquired immune deficiency syndrome-defining malignancy (HR = 2.0; 95% CI, 1.6–2.4). Conclusions Heavy alcohol use was associated with an increased risk of severe bacterial infection, as were neutrophil function-altering comorbidities. Controlled-drinking approaches should be promoted and comorbidity management should be strengthened in PWH.