Streptococcus pneumoniae is the leading bacterial cause of life-threatening infections in infants. Although antibiotic resistance affects management of pneumococcal infections, few data on patterns of resistance are available for India. We examined nasopharyngeal carriage of antibiotic-resistant pneumococci in 464 South Indian infants between 2 and 6 months. Newly acquired serotypes were screened for susceptibility to cotrimoxazole, erythromycin and penicillin using disk diffusion. Cumulative prevalence of pneumococcal carriage rose from 53·9% at 2 months to 70·2% at 6 months. The prevalence of strains that were not susceptible to penicillin, co-trimoxazole and erythromycin was 3·4, 81·1 and 37·2%, respectively. Carriage of erythromycin non-susceptible strains declined significantly between ages 4 months and 6 months (44·1 vs. 10·7%). More than 87% of the isolates screened were non-susceptible to [ges ]1 antibiotic. Serogroups/types that were most frequently non-susceptible to 1 or more antibiotics were 6, 9, 14, 19 and 23. Less than 1% of the isolates were multi-drug resistant. Widespread use of antibiotics in South India has resulted in S. pneumoniae becoming non-susceptible to some commonly used antibiotics. Monitoring trends in antibiotic susceptibility and making antibiotics available only through prescription from a health care worker may slow the spread of resistant pneumococci and improve management of pneumococcal infections in South India.