The aim of this study was to investigate whether diagnostic tests for musculoskeletal pain in the orofacial region [temporomandibular disorder (TMD) pain] are influenced by the presence of comorbid conditions, and to determine whether this influence decreases when the presence of "familiar pain" is used as outcome measure. In total, 117 patients (35 men, 82 women; 75 TMD-pain patients, 42 pain-free patients; mean age ± SD = 42.94 ± 14.17 years) were examined with palpation tests and dynamic/static tests. After each test, they were asked whether any pain was provoked and whether this pain response was familiar or not. For four clinical outcome measures (pain on palpation, familiar pain on palpation, pain on dynamic/static tests, and familiar pain on dynamic/static tests), multiple logistic regression analyses were performed with the presence of TMD pain as the primary predictor and regional (neck/shoulder) pain, widespread pain, depression, and somatization as comorbid factors. Pain on palpation was not associated with the primary predictor but with regional pain [P = 0.02, odds ratio (OR) = 4.59] and somatization (P = 0.011, OR = 8.47), whereas familiar pain on palpation was associated with the primary predictor (P = 0.003, OR = 5.23), but also with widespread pain (P = 0.001, OR = 2.02). Pain on dynamic/static tests was associated with the primary predictor (P < 0.001, OR = 11.08), but also with somatization (P = 0.037, OR = 4.5), whereas familiar pain on dynamic/static tests was only associated with the primary predictor (P < 0.001, OR = 32.37). In conclusion, diagnostic tests are negatively influenced by the presence of comorbidity. This influence decreases when the presence of familiar pain is used as outcome measure.