Plasma total homocysteine (tHcy) levels are higher in men vs. premenopausal women, but it is not known whether this difference is related to sex steroids. The effects of cross-sex hormone administration on plasma tHcy levels were therefore investigated. Plasma tHcy levels were measured at baseline and after 4 months of treatment in 17 male-to-female (M-->F) transsexuals treated with ethinyl estradiol (100 micrograms/day), in combination with the antiandrogen, cyproterone acetate (100 mg/day), and in 17 female-to-male (F-->M) transsexuals treated with testosterone esters (250 mg/2 weeks, im). In M-->F transsexuals, the plasma tHcy level decreased from geometric mean 8.2 mumol/L to 5.7 mumol/L (P < 0.001); and in F-->M transsexuals, it increased from 7.7 mumol/L to 9.0 mumol/L (P = 0.005). In M-->F transsexuals, changes in serum sex hormone-binding globulin levels correlated negatively, and changes in plasma creatinine and albumin levels correlated positively, with changes in plasma tHcy levels. In F-->M transsexuals, changes in serum 17 beta-estradiol levels correlated negatively, and changes in plasma creatinine levels correlated positively, with changes in plasma tHcy levels. We conclude that tHcy levels decrease after estrogen + antiandrogen administration to male (transsexual) subjects, and levels increase after androgen administration to female (transsexual) subjects. These changes may be both primary and secondary to the anabolic/catabolic effects, as reflected by changes of creatinine and albumin levels after cross-sex hormone administration.