Trimethoprim was specifically developed in the late 1960s as a sulphonamide potentiator and was launched in combination with sulfamethoxazole as cotrimoxazole. Laboratory data showed synergy of antimicrobial action for the combination and suggested that the use of both agents would delay the emergence of resistance. However, the tissue distribution of trimethoprim and sulfamethoxazole does not favour synergy, and resistance among common pathogens to sulfamethoxazole is high. Clinical studies comparing trimethoprim alone with cotrimoxazole for the treatment of respiratory tract and urinary tract infections have failed to show any benefit from the combination. The development of delayed resistance by use of the combination has not been substantiated. The common adverse effects seen with cotrimoxazole are gastrointestinal disturbances and skin rashes which are well described adverse effects of sulphonamides. Comparative studies suggest that these are less common with trimethoprim alone. Serious adverse effects such as liver disorders and Stevens-Johnson syndrome appear more common with cotrimoxazole. Where there is little evidence for benefit from the use of the combination, the exposure of patients to the additional risk from the adverse effects and drug interactions of 2 drugs cannot be justified. Therefore use of cotrimoxazole should be restricted to those situations such as Pneumocystis carnii pneumonia where the combination has been shown to be beneficial.