This study examined overexpression of the opioid growth factor receptor (OGFr) in squamous cell carcinoma of the head and neck and phenotypic repercussions on tumorigenicity. Tumors from 3 SCC-1 cell lines (OGFr-9, OGFr-18, OGFr-22) stably transfected with OGFr cDNA (OGFr-1) had 2.5- to 3.7-fold more OGFr than empty vector (EV) or wild-type (WT) neoplasias. No differences in OGFr number were detected between tumors of EV and WT animals. Only 16 and 28% of the mice in the OGFr-18 and OGFr-22 groups, respectively, receiving 2 million tumor cells had a measurable tumor on day 12 compared to 70% of the EV group; 25% of the OGFr-22 animals given 5 million cells expressed a tumor relative to the EV group (100%). Latencies for tumor appearance were extended by 25 and 80% for animals in the OGFr-18 and OGFr-22 groups, respectively, compared to EV animals given 2 million cells, and were lengthened by 2-fold in OGFr-22 animals injected with 5 million cells. Tumor weight of all animals overexpressing OGFr were 48-67% of EV mice, and the number of cells undergoing DNA synthesis in these tumors with amplified OGFr was reduced 46-65% of the EV group. Tumor volumes of OGFr-9 animals inoculated with 2 million cells and followed for over 7 weeks were reduced 36-70% from the WT group on days 31-54. Tumor weights on day 54 for the OGFr-9 group were 2.6-fold less than those for the WT animals. These data support OGFr gene function as a regulator of cell proliferation that impacts on tumorigenic expression of SCCHN, and suggests that molecular and pharmacological manipulation of OGFr may prevent or delay human head and neck squamous cell cancers.