Despite provisional recommendations from the World Health Organization and UNAIDS that cotrimoxazole (CTX) prophylaxis be offered to all individuals living with AIDS, including HIV-positive patients with TB, its routine use in developing countries particularly Africa has been minimal. Concerns were expressed regarding its effectiveness in areas of high bacterial resistance, that its widespread use might substantially increase bacterial cross-resistance in the community and that this intervention might promote resistance of malaria parasites to sulphadoxine-pyrimethamine. We review the current evidence on the above concerns and highlight the main operational considerations related to implementing CTX prophylaxis as a basic component of care for HIV-positive TB patients in developing countries.