Routine surveillance of pneumococcal isolates for resistance to antibiotics has revealed the emergence of an unusual pattern of multiple antimicrobial resistance in South Africa. Thirty-nine pneumococcal isolates, including 21 from clinical specimens, showed resistance to tetracycline, erythromycin, clindamycin, trimethoprim, and a combination product of trimethoprim and sulfamethoxazole sodium (co-trimoxazole), yet susceptibility to penicillin G. Multiple resistance has to date been almost invariably associated with resistance to beta-lactam antibiotics. A survey of nasopharyngeal carriage revealed carriage of an additional 21 isolates of multiply resistant pneumococci, representing 7.9% of children investigated in Johannesburg, but these organisms were not found in children in Soweto or four rural villages. We present the minimum inhibitory concentrations of 15 antimicrobial agents against 15 of these 21 strains. These findings are discussed in relation to exposure of these populations to antibiotics and to the treatment of local and systemic pneumococcal disease. Of all 60 isolates of multiply resistant pneumococci isolated to date, those fully characterized serologically belong to serotypes 6B, 14, or 19F.