Recent experimental investigations have shown that S-adenosyl-L-methionine (SAMe) reverses estrogen-induced bile secretion impairment. The mechanism of this action seems to be related to the capability of SAMe both to inactivate catecholestrogens by methylation reaction and to methylate membrane phospholipids increasing the liver plasma membrane fluidity reduced by the estrogens. Aim of this investigation was to know whether SAMe also prevents oral contraceptive-induced cholesterol supersaturation of gallbladder bile in humans. To six healthy nonobese women whose bile cholesterol saturation index increased from a mean basal value of 0.77 (SD 0.22) to 1.20 (SD 0.38) (p less than 0.01) after two cycles of treatment with oral contraceptives containing 50 micrograms ethynylestradiol, plus 250 micrograms d-norgestrel, 200 mg SAMe per os tid was administered in addition to the oral contraceptive for other two cycles. The bile cholesterol saturation index decreased to 0.88 (SD 0.26) (p less than 0.05 versus oral contraceptive value). These results indicate that SAMe antagonizes biliary lipid changes induced by estrogen-progestin containing oral contraceptive and suggest its potential usefulness in women on oral contraceptive treatment to prevent lithogenic bile secretion.