Parathyroid-like protein (PLP), or parathyroid hormone-related peptide, is a well-recognized mediator of paraneoplastic hypercalcemia (humoral hypercalcemia of malignancy syndrome). In this study we examined the expression of PLP by 40 invasive squamous cell carcinomas (SCCs) of the cervix and selected carcinomas of nonsquamous histology. Using a polyclonal antibody to human PLP, 93% of SCCs, including two tumors from patients with humoral hypercalcemia of malignancy syndrome, showed moderate to strong cytoplasmic immunoperoxidase staining for PLP. The strongest staining often was observed in areas of invasion associated with stromal desmoplasia. The small number of weak or negatively stained SCCs were all poorly differentiated tumors. Although native uninvolved squamous epithelium showed weak to moderate staining of the superficial layers, there was variable or full-thickness immunostaining in areas of dysplasia. Normal endocervical glands and stroma as well as cervical adenocarcinomas and neuroendocrine carcinomas were negative. In situ hybridization studies showed abundant PLP mRNA within SCC in patients with hypercalcemia. However, PLP mRNA was of relatively low abundance in tumors of normocalcemic patients. Ultrastructural studies showed cytoplasmic, membrane-bound, granular inclusions in tumor cells from the hypercalcemic patients. Our data suggest that increased PLP gene transcription contributes to the increased production of PLP and the pathogenesis of humoral hypercalcemia of malignancy syndrome.