The variability of the Conditioned Pain Modulation (CPM) effect can be attributed to conditioning stimulus (CS) characteristics, such as intensity, duration, unpleasantness, or affinity. This study investigates the impact of affinity and unpleasantness variables on the CPM effect using two protocols (cold water and ischemia) in the same healthy individuals (n = 54). Additional variables were also examined for their potential influence on the CPM effect. The main results are as follows: (1) a higher level of affinity and a lower level of unpleasantness for the stimuli used resulted in a stronger CPM effect; (2) significant differences were observed in the extreme categories (high and low) of both variables, whereas the 'indifferent' group did not show a clear trend; (3) within-subject analysis demonstrated that affinity for the CS had a clear impact on the CPM effect; (4) no correlations were found between the CPM effect and the additional variables, except for the extraversion variable with the CPM effect of the ischemia protocol, and CS duration variable with CPM effect in the cold water protocol; and (5) only the affinity variable explained the CPM effect in both protocols in the multiple linear regression analysis. The affinity variable was found to influence the CPM effects significantly, indicating its important role in our perception and response to pain.