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Females are at greater risk of chronic pain, and exhibit higher pain sensitivity compared to males. However, sex differences in conditioned pain modulation (CPM), a neurophysiological risk factor of chronic pain, are unclear. CPM is influenced by many factors, some of which are sex-dependent. This study explored the sex differences in CPM and its biobehavioral determinants, such as blood pressure responses, physical activity levels, pain catastrophizing scores, and conditioning stimulus intensity, in young, healthy, physically active males and females.