Administration of prostaglandins F2 alpha (PGF2 alpha) and E2(PGE2) to syngeneic mice transplanted with chemically induced squamous cell carcinoma from the same species (allograft) markedly enhanced the transplantability and cellular atypicality of these tumors. Large and invasive tumors with an atypical cellular pattern, anaplastic squamous cell carcinoma, grade IV (or fibrosarcoma), occurred in approximately 87% of mice transplanted with squamous cell carcinoma, grade I, and treated with PGF2 alpha. Similar transplanted tumors in syngeneic nontreated mice grew to a much lesser extent and remained squamous cell carcinoma, grade I. Light microscopic autoradiography and radioactivity measurements revealed a significant increase of 3H-thymidine incorporation in tumor tissue of transplanted and PG-treated mice as compared to control epidermis or to that of tumor transplanted only. Electron microscopic examination revealed that the cellular evolution in transplanted tumors treated with PGF2 alpha is shifted towards atypical fibroblasts (fibrosarcomas) which originate from the squamous cells. These findings demonstrate that PGF2 alpha and PGE2 can play an important role in tumor transplantability and cellular evolution.