This study investigated the growth-regulating effects of progesterone (Prog) on nPR-negative malignant melanoma cells and the possible mechanisms. A375 and A875 cells were cultured and treated with Prog of different concentrations. For signal transduction pathway studies, the cells were pretreated with Prog receptor antagonist (RU486, 1 x 10(-7) mol/L) or MAPK inhibitor (U0126, 5 x 10(-6) mol/L) for 1 h and then co-incubated with prog (10(-9) mol/L) for another 24 h. Indirect immunofluorescence assay, MTT, flow cytometry and Western blotting were used for assessing the nPR expression, cell growth, cell apoptosis and ERK1/2 Phosphorylation, respectively. Our results showed that lower progesterone concentration promoted the proliferation of both A375 and A875 cells, but this growth-stimulatory effect decreased at progesterone concentration of 1 x 10(-7) mol/L or higher. The response could be abolished by MAPK inhibitor U0126, but could not be blocked by progesterone antagonist RU486. Flow cytometry exhibited that high concentration ([Symbol: see text]1 x 10(-7) mol/L) progesterone increased the apoptosis of the two cells in a dose-dependent manner. The level of ERK1/2 phosphorylation was increased by a lower progesterone concentration, but reduced by a higher concentration (1 x 10(-6) mol/L). These results suggest progesterone exerts growth-regulating effects on nPR-negative tumor cells through a non-genomic mechanism.