Abstract--An inverse relation exists between omega-3 fatty acid intake and risk of cardiovascular disease development/mortality and sudden cardiac death in humans. Mechanisms underlying this cardioprotective effect are unknown, but could involve the autonomic nervous system. We tested the hypothesis that omega-3 fatty acid supplementation ("fish oil") would reduce muscle sympathetic nerve activity (MSNA) at rest and attenuate increases during physiological stressors. MSNA (peroneal microneurography) was measured during rest, ischemic handgrip to fatigue (IHG), and a cold pressor test (CPT). Measurements were obtained before (PRE) and after (POST) 1 month of daily ingestion of either fish oil (experimental group, n=9) or olive oil capsules (control group, n=9). MSNA at rest was comparable PRE and POST in control (3±1 versus 3±1 bursts/30 seconds) and experimental (4±1 versus 5±1 bursts/30 seconds) subjects. IHG and CPT increased MSNA in both groups PRE and POST. MSNA, arterial blood pressure, and heart rate responses to the stressors were similar PRE and POST in the control group. In contrast, MSNA responses to IHG (4±2 and 9±2 bursts/30 seconds; P<0.05 for PRE and POST, respectively) and CPT (4±1 versus 10±2 bursts/30 seconds; P<0.05) were augmented after omega-3 fatty acid supplementation whereas arterial blood pressure and heart rate responses were unchanged. These data indicate that 1 month of omega-3 fatty acid supplementation does not change MSNA at rest but augments sympathetic outflow to physiological stressors. The mechanism underlying augmented MSNA responses to physiological stressors after omega-3 fatty acid supplementation is unknown, but may involve impaired peripheral vasoconstriction.