To investigate the mechanism of the antifertility action of sulfasalazine, we prospectively measured sperm density, motility, hamster oocyte penetration capacity, and reactive oxygen species production in six men with inflammatory bowel disease being treated with sulfasalazine and 8 and 16 weeks after changing to 5-aminosalicylic acid (5-ASA). An improvement was observed after changing to 5-ASA in those with poor (n = 3), but not in those with normal (n = 3), sperm function on sulfasalazine. There was no correlation between reactive oxygen species production or acetylator phenotype with egg penetration capacity, sperm motility, or sperm density. We conclude that the mechanism of impairment and recovery of sperm function on and off sulfasalazine treatment is not related to an excess in reactive oxygen species.