Lymphocyte apoptosis increases following maximal exercise. Estrogen hormones (E2) have been shown to protect lymphocytes from apoptosis in vitro, but it is unknown whether they can attenuate the apoptotic response to maximal exercise. The purpose of this study was to examine the effect of menstrual cycle variation on exercise-induced lymphocyte apoptosis in humans following exercise. Untrained healthy young men and regularly menstruating women not using hormonal contraceptives volunteered for the study. Women performed a maximal effort treadmill test for VO2 max once in the follicular phase (FOL) and once in the mid-luteal phase (ML) of their cycles. Men completed two VO2 max tests with periods of time between tests matched to those of the female subjects. Blood was collected before (PRE) and immediately after exercise (POST), and analyzed for apoptotic lymphocytes and estradiol. E2 concentrations in women were significantly greater during ML versus during FOL, both PRE and POST (p<0.0001). The percent of exercise-induced lymphocyte apoptosis was similar between women (23.2%+/-1.0%) and men (21.5%+/-0.4%). In women, the apoptotic response to maximal exercise was similar regardless of menstrual cycle phase (FOL=23.7%+/-0.9%, ML=22.7%+/-1.1%). Although elevated female sex hormones in vitro may exert anti-apoptotic effects, these data suggest that in vivo concentrations confer no protection to lymphocytes during exhaustive exercise.