Despite the prevalence of cancers of the head and neck, survival rates have not changed in the past few decades. Recent work has implicated peptide growth factors and their receptors in the genesis and progression of head and neck squamous cell carcinoma. Opioid growth factor (OGF, [Met5]-enkephalin) is a tonically active, autocrine and/or paracrine produced, inhibitory factor that influences the growth of normal and abnormal cells and tissues. This peptide interacts with the zeta (zeta) opioid receptor to modulate cellular proliferation, migration, and survival. Both OGF and the zeta receptor are present in mammalian tongue epithelium and skin, and modulate DNA synthesis. In the present study we examined the presence and distribution of OGF and the zeta opioid receptor in the head and neck squamous cell carcinomas from seven individuals. All specimens expressed this growth factor and its receptor regardless of tumor stage, location, and histologic grade. Immunoreactivity for both OGF and the zeta receptor were associated with the cytoplasm but not the nucleus in cells of each of these carcinomas. Our findings that a potent negative growth regulator and its receptor are present in head and neck squamous cell carcinoma lead us to suggest that OGF may modulate the growth of these types of cancers.