Background: Febrile illness with suspected blood stream infection (BSI) is a common reason for admission to hospital in Africa and blood cultures are therefore an important investigation. Data on the prevalence and causes of community acquired BSI in Africa are scarce and there are no studies from South Africa. There are no validated clinical prediction rules for use of blood cultures in Africa. Methods: A prospective observational cohort study of patients attending 2 urban emergency departments in Cape Town, South Africa. The decision to take a blood culture was made by the attending clinician and information available at the time of blood draw was collected. Bottles were weighed to measure volume of blood inoculated. Results: 500 blood culture sets were obtained from 489 patients. 39 (7.8 %) were positive for pathogens and 13 (2.6 %) for contaminants. Significant independent predictors of positive cultures were diastolic blood pressure <60 mmHg, pulse >120 bpm, diabetes and a suspected biliary source of infection, but not HIV infection. Positive results influenced patient management in 36 of 38 (95 %) cases with the organism being resistant to the chosen empiric antibiotic in 9 of 38 (24 %). Taking <8 ml of blood was predictive of a negative culture. The best clinical prediction rule had a negative predictive value (NPV) of 92 % which is unlikely to be high enough to be clinically useful. Discussion: Blood cultures taken from patients attending emergency departments in a high HIV prevalent city in South Africa are frequently positive and almost always influence patient management. At least 8 ml of blood should be inoculated into each bottle. Conclusion: Blood cultures should be taken from all patients attending EDs in South Africa suspected of having BSI particularly if diabetic, with hypotension, tachycardia or if biliary sepsis is suspected.