The increasing use of mobile phone communication has raised concerns about possible health hazard effects of microwave irradiation. We investigated damage and differentiation of PC12 mutant cells (PC12m3 cells) caused by microwave irradiation. The frequency of neurite outgrowth induced by 2.45 GHz (200 W) of microwave irradiation was approximately 10-fold greater than that in non-irradiated control cells. Microwave treatment of PC12m3 cells resulted in an increased level of p38 MAPK activity. Similarly, CREB activity was seen in PC12m3 cells but not in PC12 parental cells. Heat shock treatment at 45°C had a strong toxic effect on PC12 parental cells, whereas PC12m3 cells showed stronger resistance than PC12 parental cells to temperatures of both 45°C and 42°C. Although microwave irradiation at 200 W had no toxic effect on PC12m3 cells, microwave irradiation led to toxicity in PC12 parental cells. Moreover, microwave irradiation at 100 W, rather than having a toxic effect, induced proliferation of PC12m3 cells despite having no effect in PC12 parental cells. These findings indicate that p38 MAPK is responsible for the survival and proliferation of PC12m3 cells and might induce neurite outgrowth via a CREB signaling pathway in PC12m3 cells subjected to microwave irradiation.