In recent years, it has been suggested that mandibular malposition, resulting from either malocclusion or improper occlusal reconstruction, is associated with physical complaints, while all stress information is combined at the hypothalamus. In this study, we assessed the hypothalamic activation in a malocclusion model in healthy humans. Eight healthy subjects with normal occlusion participated in this study. Their hypothalamic activities during clenching in a mandibular retrusive position, which is one form of malocclusion, were examined with functional magnetic resonance imaging (fMRI). Individual analyses showed that clenching at the mandibular retrusive position significantly increased the blood oxygenation level-dependent (BOLD) signals in the hypothalamus in two of the subjects. The results suggest that depending on the individual, mandibular malposition affects the hypothalamus which responds by directly inducing stress. In the future, fMRI may serve as a useful tool for individual diagnosis, as sensitivity of the malocclusion depends on the individual response.