Abstract Background and aims: Exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM) are assumed to reflect descending pain inhibition. Potential interactions between EIH and CPM may be important in the therapy of chronic pain, as reduced CPM and increased pain after exercise are frequently observed. This study compared the EIH response after CPM was activated using a cold pressor task with the EIH response after a control condition. Methods: Thirty-one participants (age: 27.7±9.8; 15 female) completed two sessions: a cold pressor task (CPT) session, i.e. testing EIH with preceding CPM activation induced using a 2 min CPT at approximately 2°C, and a control session, i.e. testing EIH after a control condition (2 min of quiet rest). EIH was induced using a 15 min bicycling exercise at a target heart rate corresponding to 75% VO2 max. Repeated measures ANOVAs on pressure pain thresholds (PPTs) at the hand, back and leg were used to determine the effects of exercise after the cold pressor test and control condition. Furthermore, correlations between CPM and EIH, in the CPT session as well as control session, were calculated at each assessment site. Results: A significant time x condition interaction (F(1, 30)=43.61, p<0.001, partial η2=0.59), with Bonferroni-corrected post-hoc t-tests showed that PPTs increased after exercise in the control session (p<0.001), but not in the CPT session (p=0.125). Furthermore, there was a small positive correlation of EIH in the control session and CPM at the hand (r=0.37, p=0.043). There was a moderate negative correlation of EIH in the CPT session and CPM at the hand (r=−0.50, p=0.004), and smaller negative correlations at the back (r=−0.37, p=0.036) and at the leg (r=−0.35, p=0.054). Conclusions: Attenuated EIH after the CPM activation in comparison to a control condition suggests that EIH and CPM may share underlying pain inhibitory mechanisms on a systemic level. This assumption is further supported by the finding of small to moderate significant correlations between EIH and CPM at the hand. The attenuated EIH response furthermore suggests that these mechanisms are exhaustible, i.e. that its effects decline after a certain amount of inhibition. Implications: In patients with chronic pain, assessing the current capacity of the descending pain inhibitory system – as indicated by the CPM response – may aid to make better predictions about how patients will respond to exercise with respect to acute pain reduction.