Background: Smoking increases cardiovascular risk in young women and eliminates the protective effect of the premenopausal state. Increased sympathetic nervous system (SNS) activity is associated with increased cardiovascular risk. One potential mechanism by which smoking increases risk is through chronic SNS activation. It has been reported that premenopausal women have high SNS activity during the midluteal (ML) phase, which falls to low levels during the early follicular (EF) phase. We tested the hypothesis that smoking disrupts this fall in SNS activity during the EF phase. Methods and Results: We measured blood pressure and muscle sympathetic nerve activity (MSNA) using microneurography in 11 premenopausal female smokers and 11 age-matched nonsmoking controls at two separate times during the ovarian cycle: ML phase (8-10 days after the luteinizing hormone (LH) surge), and EF phase (days 1-4 of the menstrual cycle). The change in MSNA from the EF phase to the ML phase was significantly different between the smoking and nonsmoking groups (p=0.036). Whereas there was a significant decrease in MSNA from the ML phase to the EF phase among nonsmoking controls (22.7±3.3 vs 17.9±2.8 bursts/min, p=0.012), MSNA remained elevated during the EF phase in smokers (22.5±3.8 vs 26.8±4.0 bursts/min, p=0.28). Surprisingly, mean arterial pressure (MAP) was significantly lower during the ML phase than in the EF phase in both nonsmokers (p=0.0080) and smokers (p=0.0094). Conclusions: Smoking disrupts the ovarian pattern of SNS activity by preventing the normal fall in MSNA during the EF phase of the ovarian cycle. Such chronic alterations may contribute to the pathogenesis of cardiovascular risk in young smoking females.