The reasons for combining trimethoprim (TMP) with sulfonamides (SUL) are still mainly theoretical but are supported by results from experimental infections and treatment of specific pathogens in humans, such as Branhamella catarrhalis, Neisseria gonorrhoeae, Brucella, Nocardia asteroides and perhaps Bordetella pertussis and Chlamydia trachomatis. Addition of SUL to TMP confers a therapeutic advantage also in patients with complicated urinary tract infection but probably not in young women with acute cystitis. Conditions that may enable TMP-SUL synergy in vivo can be expected to occur only in occasional cases of infection due to staphylococci, streptococci, Haemophilus or enteric bacteria. This fact together with ethical problems and availability of alternative therapies make further evaluations of the clinical significance of the SUL component of TMP-SUL very difficult. Although the use of TMP alone has shown promise in exacerbations of chronic bronchitis the role of the SUL component in TMP-SUL treatment of infections outside the urinary tract remains to be defined in comparative clinical trials.