Aims: To investigate systematically whether conditioned pain modulation (CPM) evoked by tonic mechanical stimuli applied to the craniofacial region is intensity-, assessment site-, and gender-dependent. Methods: Twenty healthy men and 20 women participated in four sessions. Tonic painful mechanical stimulation was applied to pericranial muscles by a mechanical headband pressure device. The pressures applied to four probes were adjusted via pain feedback from a 0 to 10 electronic visual analog scale (VAS) to generate different pain levels (VAS0, VAS1, VAS3, or VAS5) for 10 minutes. Pressure pain thresholds (PPTs) and pressure pain tolerance thresholds (PPTols) were assessed from right masseter muscle and left forearm by pressure algometry before, during, immediately after, 10 minutes after, and 20 minutes after the conditioning stimulus (CS). Data were analyzed with multilevel ANOVAs. Results: PPT values normalized to baseline recordings were not dependent on gender or assessment site, but dependent on intensity (P .001) and time (P .001). The most painful CS (VAS5) was associated with the highest PPT increases (32.6% ± 3.3%, mean value for the two assessment sites and two genders) during CS compared to all other intensities of CS (P .001). PPTol values normalized to baseline recordings were also not dependent on gender or assessment site, but dependent on intensity (P .001) and time (P .001). The most painful CS (VAS5) was associated with higher PPTol increases (11.2% ± 2.8%, mean value for the two assessment sites and two genders) during CS (P .001). Conclusion: CPM evoked by mechanical stimulation of the craniofacial region is intensity-dependent but not assessment site- or gender-dependent. Keywords: conditioned pain modulation (CPM), diffuse noxious inhibitory control (DNIC), experimental craniofacial pain, gender differences, trigeminal system