Co-trimoxazole is still widely used for indications where trimethoprim alone is equally effective. The pharmacological rationale of the combination of trimethoprim and sulphamethoxazole involves synergistic action of the two drugs. This is true only from a laboratory point of view; several considerations have led to the conclusion that the synergism between the two components is of only in vivo marginal importance in determining the clinical efficacy of co-trimoxazole. This is due to a greater tissue affinity of trimethoprim compared to that of sulphamethoxazole and, therefore, to the different tissue concentration ratios obtained in vitro and in vivo. Another claim sustaining the combination is the prevention of developing resistance to trimethoprim; however, there is no substantial clinical evidence to support this claim. It does seem likely that trimethoprim has protected against the emergence of that sulphonamide resistance. This slight benefit is outweighed by the disadvantages of the combination, mainly consisting of the occurrence of adverse events due to the sulphonamide moiety. Consequently, the incidence and severity of the adverse events seen with co-trimoxazole should be reduced by using trimethoprim alone. There are only a few cases where co-trimoxazole is better than trimethoprim: toxoplasmosis, brucellosis, nocardiosis, chancroid and pneumonia due to Pneumocystis carinii. For the other and many common infections, scientific rationale, economic and clinical reasons dictate that trimethoprim is superior to co-trimoxazole.