There are few data on the epidemiology of invasive pneumococcal disease in Africa. We undertook a prospective study of these infections in Kumasi, Ghana, collecting clinical data on all patients with laboratory-confirmed pneumococcal meningitis, pneumonia or systemic sepsis associated with bacteraemia. A total of 140 cases were identified in the period from January 2002 to April 2005. The disease was most prevalent among patients <5 years of age and immediately following the peak of the harmattan wind. The majority of patients were treated with a combination of antibiotics, in part reflecting concerns regarding antibiotic resistance. Mortality was high (47%), with no evidence of an improved prognosis compared with earlier studies in the region. Although most isolates of pneumococci were resistant to tetracyclines and co-trimoxazole, there was no high-level resistance to penicillin and only 12% of isolates showed intermediate level resistance. Serotype 1 was the most common serotype (36%), whilst intermediate-level penicillin resistance was associated with serotype 14. Theoretical coverage by existing 7-, 9-, 11- and 23-valent vaccines was 26%, 63%, 64% and 76%, respectively. Vaccination may improve control of pneumococcal disease in Ghana, although modified vaccine formulations are required for local use.