The antimicrobial susceptibility of 64 strains of S. pneumoniae obtained from three hospitals in Porto Alegre, Brazil, isolated between 2004 and 2005, was determined, using the agar-dilution method. The prevalence of resistant (intermediate and full resistance) strains to trimethoprim/sulphamethoxazole, penicillin, tetracycline, erythromycin, chloramphenicol, and ceftriaxone were 68%, 28%, 18%, 15%, 3%, and 1%, respectively. All strains were susceptible to vancomycin. Among 18 penicillin-resistant strains, 7 were resistant to at least two other antimicrobial drugs. All erythromycin-resistant strains, except one, contained the erm(B) and/or mef(A/E) genes, with a predominance of the former. The resistance rate to penicillin and erythromycin in Porto Alegre remained stable. The combination of trimethoprim/ sulphamethoxazole should not be recommended to treat pneumococcal infections, because of the high rate of resistant strains.