Pneumococcal pneumonia and meningitis are common infectious disease problems in people who are HIV seropositive in southern Africa. For many years two inexpensive antibiotics, penicillin and trimethoprim-sulphamethoxazole (TMP-SMX) had been effective in treatment, but recently resistance to these agents has been reported from many parts of the world. This study was designed to determine the antimicrobial resistance patterns in invasive pneumococci from hospital patients in Harare, Zimbabwe. A total of 160 isolates of Streptococcus pneumoniae from blood cultures and CSF cultures were examined. The isolates came from adults and children in hospital in Harare between 1994 and 2000. The majority of isolates came from HIV positive adults (74%) and children (75%). Isolates of pneumococci with an MIC of 1.0 mg/l or more were first seen in 1997 and by 2000 they made up 35% of all isolates. Significantly more isolates from HIV seropositive patients (50%) showed reduced susceptibility to penicillin compared with isolates from HIV seronegative patients (16%), and high level resistance (MIC 1.0 mg/l or higher) was found in 16% isolates from HIV positive patients compared with 6% isolates from HIV seronegative patients. Resistance to TMP-SMX was common, with more than 50% isolates from HIV positive and HIV negative patients having reduced susceptibility to this antibiotic combination.