Cytotoxic action of various prostaglandins (PGs) was examined on the PAM 212 transformed mouse epidermal cell line, and delta 7-PGA1 was found most active. delta 7-PGA1 exerted a dose-dependent inhibition of PAM 212 cell growth over 0.1 microgram/ml (0.3 microM). At 1.6 microgram/ml (4.6 microM) growth was completely inhibited, and the number of viable cells decreased remarkably during culture. The concentration needed for 50% growth inhibition (IC50) value of delta 7-PGA1 on PAM 212 cell growth was calculated as 0.4 microgram/ml (1.1 microM). At this concentration, the DNA synthesis in 24- and 48-h cultured cells was decreased to a half of the level in the control cells, and microscopically, remaining cells showed degenerative changes with many vacuoles in their cytoplasm. Prostaglandin D2, a major PG in mast cells, also showed potent cytotoxic activity. However, this action was expressed as 9-deoxy-delta 9,12-13,14-dihydro-PGD2 (delta 12-PGJ2), which was converted from PGD2 in plasma, and had a 3-fold stronger growth inhibitory activity than PGD2; the IC50 values of PGD2 and delta 12-PGJ2 were 2 micrograms/ml (5.7 microM) and 0.75 microgram/ml (2.1 microM), respectively. Among other PGs tested, PGA2 showed a comparable growth inhibitory activity, and PGB2, PGE1, and PGE2 less but significant activity. Prostaglandin F2 alpha and PGI2 however, had no such effect on cell proliferation at 5 micrograms/ml (14.3 microM) concentration, suggesting that cyclopentenone structure is an essential moiety of PG derivatives for cell growth inhibition. This cytotoxic action of delta 7-PGA1 and delta 12-PGJ2 appears to be independent of cyclic-AMP, since these PGs were virtually inactive in raising intracellular cyclic-AMP levels in PAM 212 cells.