Most odorants not only stimulate olfactory receptor neurons but also activate the intranasal trigeminal nerve. The simultaneous activation of the olfactory and the trigeminal system leads to an interaction in the brain. Therefore, assessment of the trigeminal impact of odorants may be difficult in subjects with a normal sense of smell. To obtain a deeper insight into both, mechanisms of changes in trigeminal sensitivity in anosmic patients and interactions between the olfactory/trigeminal systems in healthy subjects, 21 patients with isolated congenital anosmia (ICA) were investigated in this series of explorative, hypothesis-generating experiments and compared with 35 healthy controls. Trigeminal sensitivity was measured by psychophysical (lateralization task, intensity ratings) and electrophysiological (trigeminal event-related potential, negative mucosal potential) means. ICA patients were found to have higher peripheral activation than controls. On central levels, however, similar responsiveness to trigeminal stimuli was found in ICA patients when compared with healthy subjects. The results of the study are discussed by proposing a model of mixed sensory adaptation/compensation in the interactions between olfactory and the trigeminal system.