Impaired cell-mediated immune response is commonly seen in patients with squamous cell carcinoma of the head and neck. This immune defect has been associated with poor clinical performance. Recent evidence indicates an immunoregulatory action for cimetidine. For this reason, the effect of this medication on delayed hypersensitivity reactions in previously untreated patients with squamous cell carcinoma of the head and neck was studied. Patients hyporesponsive to an initial skin test battery were treated with cimetidine. A statistically significant increase in delayed hypersensitivity responses on repeated skin testing during cimetidine hydrochloride therapy was observed. Four of these patients who converted their skin tests while receiving cimetidine were again studied one to two weeks after cessation of therapy. All four returned to their precimetidine treatment status. These skin test response results suggest that histamine-mediated suppression of immune response occurs in patients with head and neck cancer. Cimetidine should be considered as an immunomodulator in patients with squamous cell carcinoma of the head and neck.