Aims: To test the hypothesis that the effects of an experimental occlusal interference differ between individuals reporting a high or low frequency of wake-time oral parafunctions. Methods: Study participants reporting very high (HFP group; n = 10) or very low (LFP group; n = 10) levels of oral parafunctions were selected by means of a questionnaire administered to 200 medical students. The selected participants wore an experimental occlusal interference in a single-blind longitudinal study, which comprised different occlusal conditions: interference free (IFC) and active occlusal interference (AIC). Assessments included clinical examination, measurements of nonfunctional tooth contacts, state and trait anxiety, and visual analog scale scores for occlusal discomfort, masticatory muscle pain, and headache. Data were analyzed by repeated measures twoway analysis of variance on ranked data, followed by calculation of within- and between-group differences using Friedman tests and Mann-Whitney tests, respectively. Results: During AIC, the frequency of nonfunctional tooth contacts significantly decreased in both groups (median [interquartile range, IQR]: in HFP from 55.3% [60.0%] to 31.1% [33.5%], P = .03; in LFP from 31.8% [32.4%] to 14.0% [22.8%], P .01), the decrease being more pronounced in LFP than in HFP (P .01). Trait anxiety was significantly higher (P = .01) in the HFP group (median, IQR = 22.5, 9.0) than in the LFP group (median, IQR = 19.0, 3.0). The interference caused more occlusal discomfort in the HFP group than in the LFP group (P = .02) and was associated with a significant increase of masticatory muscle pain (P = .05) and headache (P = .04) only in the HFP group. Conclusion: The application of an experimental occlusal interference has a different effect in individuals reporting a high or low frequency of oral parafunctions.