Purpose There is considerable interindividual variability in the perception of pain. Given that pain management is a major public health problem, gaining insight into the underlying physiology of these perceptual diferences is important. We tested the hypothesis that when interindividual variability in initial muscle sympathetic nerve activity (MSNA) responses to a cold pressor test (CPT) is identifed, the divergent responses will be linked to diferences in pain perception in healthy young men and women. Methods In the supine position, blood pressure (BP) and MSNA were measured at baseline and during a 2-min CPT. Immediately following the CPT, pain was rated (range 0–10). Results Two groups were established: positive responders (Pos, n=12) and negative responders (Neg, n=12) based on the initial (frst 30 s) MSNA response profles (Pos: 12±9, Neg: −3±3 bursts/min, P<0.0001). MSNA response profles throughout the CPT were diferent between groups (P<0.0001). Peak MSNA increases were diferent (Pos: 27±11, Neg: 9±5 bursts/min, P<0.0001) and corresponded with initial MSNA responses (R2=0.6881, P<0.0001). Blood pressure responses were also diferent throughout the CPT (P<0.0001). Most importantly, the perception of pain induced by the CPT was diferent between the two groups (Pos: 8±1, Neg: 4±1, P<0.0001). Conclusions The results indicate that in healthy young men and women, there are divergent initial sympathetic neural responses to a given painful stimulus that are linked to the magnitude of pain perception. These fndings highlight the distinctive sympathetic patterns that may contribute to the considerable interindividual variability in the perception of pain.