It is unclear why men have a higher incidence of calcium oxalate nephrolithiasis than women. This study examined the role of sex hormones on urinary oxalate excretion and kidney stone formation in an experimental model of urolithiasis. Adult male and female Sprague Dawley rats with different sex hormone modulations were given 0.75% ethylene glycol for 2 wk to induce hyperoxaluria and kidney calcium oxalate crystal deposition. The study groups were: intact male and female rats; castrated male and female rats; intact male or female rats with opposite sex hormone implants; and castrated male and female rats with either testosterone or estradiol implants. Overall, a significant negative correlation between urinary oxalate and plasma estradiol/testosterone ratio was found. None of the estradiol-implanted rats, whether male or female, intact or castrated, developed kidney crystal deposits. The three groups of testosterone-implanted rats had a 43 to 88% rate of kidney calcium oxalate crystal deposition. These results indicate that androgens increase and estrogens decrease urinary oxalate excretion, plasma oxalate concentration, and kidney calcium oxalate crystal deposition. These findings may partly explain why nephrolithiasis is a predominantly male disease.