The epidemiology and natural history of bacterial infections among ambulatory patients with advanced human immunodeficiency virus (HIV) disease has not been well described. In this prospective study, 394 subjects were enrolled and followed at 8-week intervals for a median of 21 months. During follow-up, 164 (42%) of 394 patients developed at least 1 bacterial infection. The most common infections were sinusitis, bacterial pneumonia, skin and soft tissue infection, and bronchitis. Serious bacterial infections (defined as bacterial pneumonia, bacteremia, or deep visceral abscess) were reported by 56 subjects (14%). Female sex, age of <40 years, and Karnofsky score of < or =80 were independent risk factors for bacterial infections. Prophylaxis with clarithromycin, trimethoprim and sulfamethoxazole, or both had significant protective effect. The occurrence of any confirmed bacterial infection was associated with a significantly increased risk of mortality. This study documents that bacterial infections are common among patients with advanced HIV disease, especially among women.