PURPOSE: Heart rate variability (HRV) estimates the autonomic nervous system (ANS) influence on the heart and appears sex-specific. Sensory afferents exhibit sex-specificity; although, it is unknown if Capsaicin, an agonist for transient receptor potential vanilloid channel-1 (TRPV(1)), alters cardiac ANS activity in a sex-dependent manner, which could be important given the predictive nature of HRV on risk of developing hypertension. Thus, we explored if there was sex-specificity in the effect of capsaicin on estimated cardiac ANS activity. METHODS: HRV was measured in 38 young males (M: n = 25) and females (F: n = 13), in a blinded-crossover design, after acute ingestion of placebo or capsaicin. Resting HR, RR-interval, root-mean-square of successive differences (RMSSD), natural log-transformed RMSSD (LnRMSSD), standard deviation of n-n intervals (SDNN), number of pairs of successive n-n intervals differing by > 50 ms (NN50), and percent NN50 (PNN50) were obtained using standard techniques. RESULTS: Significant sex differences were observed in mean HR (M: 59 +/- 9.3 vs. F: 65 +/- 12 beats/min, p = 0.036, eta(2) = 0.098), minimum HR (M: 47 +/- 8.3 vs. F: 56 +/- 12 beats/min, p = 0.014, eta(2) = 0.124), and NN50 (M: 177 +/- 143 vs. F: 29 +/- 17, p < 0.001, eta(2) = 0.249). There was a significant interaction of sex*treatment (p = 0.02, eta(2) = 0.027) for RMSSD, where males increased (78 +/- 55 vs. 91 +/- 64 ms), and females decreased (105 +/- 83 vs. 76 +/- 43 ms), placebo vs. capsaicin. CONCLUSION: This controlled study recapitulates sex differences in HR and HRV, but revealed a sexual dimorphism in the parasympathetic response to capsaicin, perhaps due to differing TRPV(1)-afferent sensitivity, highlighting a potential mechanism for differential regulation of hemodynamics, and CVD risk, and should be considered in future studies.