Nasopharyngeal swabs were taken from 906 Malawian children <5 years old visiting rural health clinics. Pneumococcal colonization was high, 84% among all children, and occurred early, 65% of it in children <3 months old. Among pneumococcal isolates 46% were nonsusceptible to trimethoprim-sulfamethoxazole, and 21% were nonsusceptible to penicillin. Trimethoprim-sulfamethoxazole use in the previous month was a risk factor for trimethoprim-sulfamethoxazole and penicillin nonsusceptibility. Forty-three percent of isolates were serotypes included in the 7-valent pneumococcal conjugate vaccine, and 37% were vaccine-related serotypes, particularly 6A and 19A.