Exercise effects on natural killer cell (NK) activity in men appear to be intensity dependent, but there is very little data in women. We tested the effect of high versus moderate-intensity exercise relative to non-exercising controls on NK cytolytic activity (NK activity) in women using oral contraceptives. Subjects (n = 8) participated in 3 treatments consisting of 25 min of cycle ergometer exercise at 80% (HI-INT) and 40% (MOD-INT) VO2max, and a 25 min control (CON) session in which the subject remained seated on the cycle ergometer, but did not exercise. Blood was obtained prior to exercise, immediately after, and at 90 min and 3 h after exercise. During CON, NK activity gradually increased and cortisol gradually decreased during the approximately 3.5 h experimental period. Relative to CON, HI-INT increased NK activity, %CD56+ (NK) cells, and plasma norepinephrine immediately post exercise (p < or = 0.05). There was also a trend for decreased NK activity at 90 min (p = 0.075). No differences among treatment groups were found by 3 h post exercise. In MOD-INT, there were no differences from CON in any variable at any time. These data suggest that the typical NK response to intensive exercise in men, which consists of a brief increase followed by a more prolonged suppression, also occurs in women using oral contraceptives. However, it is important to use time-matched control measurements in determining this response.