OBJECTIVES: To describe the incidence and aetiology of septicaemia, and antimicrobial drug resistance in HIV-infected and uninfected individuals, and the impact of antiretroviral therapy (ART) on septicaemia. METHODS: Between 1996 and 2007, we followed up a rural population-based cohort of HIV-infected and uninfected participants. The aetiology and incidence of septicaemia, and antimicrobial drug resistances were determined. ART became available in 2004, and its impact on the incidence of septicaemia was examined. RESULTS: The overall septicaemia incidence (per 1000 pyrs) was 32.4 (95% CI 26.2-40.6) but was only 2.6 (95% CI 1.3-6.2) in HIV-negative patients and 67.1 (95% CI 53.4-85.4) in HIV-positive patients not on ART. Among those on ART, the overall incidence was 71.5 (95% CI 47.1-114.3), although it was 121.4 (95%CI 77.9-200.4) in the first year on ART and 37.4 (95%CI 18.9-85.2) in the subsequent period. Septicaemia incidence was significantly associated with lower CD4 counts. The commonest isolates were Streptococcus pneumoniae (SPN, n = 68) and Non-typhi salmonellae (NTS, n = 42). Most SPN isolates were susceptible to ceftriaxone and erythromycin, while resistance to cotrimoxazole and penicillin was common. All NTS isolates were susceptible to ciprofloxacin, but resistance to cotrimoxazole and chloramphenicol was common. CONCLUSIONS: Septicaemia incidence was higher in HIV-infected than in HIV-uninfected participants, and it remained high for some time among those who started ART. Starting ART earlier at higher CD4 counts is likely to lead to lower septicaemia incidence. Both SPN and NTS, the commonest isolates, were resistant to most commonly available antimicrobials. Blood culture laboratory surveillance systems to monitor antibiotic susceptibility and inform treatment guidelines are needed in Africa.