The aim of this study was to develop a model to evaluate the efficacy of drugs with expected sweat-reducing properties in healthy subjects in order to select candidate drugs for the systemic treatment of primary generalized hyperhidrosis. A randomized, double-blind, placebo-controlled cross-over study was performed in 8 healthy subjects. Sweating was induced by exercise. The degree of sweating at different exercise levels was determined by measurement of transepidermal water loss. Either the anticholinergic drug oxybutynin or placebo was given before measurements started. No statistically significant differences in transepidermal water loss between active treatment and placebo were found at the different exercise levels. This is noteworthy, as oxybutynin has been proven successful in patients with generalized hyperhidrosis. Thus, the present model does not mimic the situation in patients with primary generalized hyperhidrosis. This may be because this form of hyperhidrosis is not caused only by sympathetic overactivity, as described in the literature, but is based on more complex mechanisms. Further investigations are required fully to understand the pathophysiology of primary generalized hyperhidrosis in order to develop effective human test models.