An open, randomized trial was carried out in 50 patients with severe respiratory tract infections due to various pathogens to compare the effectiveness and tolerability of co-trimoxazole and cephalexin. Patients were divided into two groups, each of 25, and treated for 15 days with either 1 tablet of co-trimoxazole (160 mg trimethoprim plus 800 mg sulphamethoxazole) every 12 hours or 1 capsule of cephalexin (500 mg) every 6 hours. The results of bacteriological and radiological investigations before and after 10 and 15 days of treatment showed that, although response to cephalexin was somewhat faster, both drugs were equally effective and well-tolerated over the full treatment period and there was good correlation between the laboratory findings as well as clinical improvement in symptoms. Taking the cost-benefit ratio into consideration, it is suggested that co-trimoxazole should be used for first-line therapy in respiratory tract infections and cephalexin only as a reserve drug for infections which do not respond to the routine use of co-trimoxazole.