We reviewed 153 episodes of invasive pneumococcal disease involving 147 hospitalized patients with and without human immunodeficiency virus (HIV) disease to examine and compare epidemiologic and clinical features, capsular serotypes, and antibiotic susceptibility patterns. HIV infection was the most common risk factor for invasive pneumococcal disease. Pneumococcal disease in HIV-infected individuals was characterized by the greater frequency with which pneumonia was the source of bacteremia (90% vs. 63%) (P < .01) and an increased recurrence rate (15% vs. < 1%) (P < .01). The overall mortality rate was 12% and did not vary by HIV serostatus. Capsular-type data were available for 149 episodes; 90% of the types were among those found in the polyvalent pneumococcal vaccine. The four most common capsular types causing invasive disease were 14, 6b, 9v, and 22f; capsular type 9v was significantly more common among HIV-infected patients (P < .01). Penicillin-resistant isolates were identified in 7.2% of all cases, and their presence did not vary by HIV status; 20% of isolates from cerebrospinal fluid were resistant. The majority of the resistant isolates were of capsular type 9v. Given the worldwide increase in both HIV and penicillin-resistant pneumococcal infections, better preventative and therapeutic strategies are greatly needed.