Chronic ultraviolet (UV) exposure induces clones of cells overexpressing mutant p53 in the interfollicular (IF) epidermis and subsequently squamous cell carcinomas (SCCs) with similar p53 mutations. Mutated p53 may give cells growth advantage over neighbouring cells by impaired apoptosis. We tested this by UV overexposure of skin laden with p53-mutant clones and assessed the impact on subsequent tumour development. P53-mutant clones were induced in two groups of hairless SKH1 mice by daily exposures (500 J/m(2) UV from TL12 lamps) for 28 days. On day 29, one group was overexposed (to 10 kJ/m(2) UV), whereas the control group received the regular daily dose. After 1 week of recovery, the daily exposures were resumed in both groups to induce SCCs. UV overexposure forced the entire IF basal layer into caspase-3-driven apoptosis while leaving overlying layers with sunburn cells intact. No apparent regions were spared from apoptosis. Pulse-chase BrdU labelling showed the IF epidermis to be repopulated from the hair follicles (remaining p63 positive). One week after overexposure, the p53-mutant clones had virtually disappeared (0.6, 95% confidence interval 0.5-0.8 per mouse versus 102, 59-179, without overexposure). Tumour development was significantly delayed after UV overexposure (P < 0.0001) by an average of 27 days (standard error of the mean 3); a period matching that of daily exposures preceding the overexposure. Thus, we found that UV-induced ablation of the IF epidermal basal layer eliminates p53-mutant clones and resets UV carcinogenesis. Furthermore, and in contrast with earlier reports, our data show that UV-induced p53-mutant clones and SCCs originate from the IF epidermis.