Sun-exposed skin of Caucasians harbors thousands of p53-mutated clones, which are clinically invisible. Using whole mount immunostaining for p53 or Ki67 antigens, p53 sequencing, and loss of heterozygosity analysis, we have further characterised these clones. Loss of heterozygosity for the alleles examined is uncommon with the exception of 9q, which occurred in 28.3% of the samples. P53 clones are more common and larger in individuals with basal cell carcinoma than in control subjects (p < 0.03). Loss of heterozygosity is also more common in clones from individuals with basal cell carcinoma than in clones from subjects without a history of basal cell carcinoma, as would be expected if both relate to ultraviolet radiation exposure. p53 sequencing of clones is in keeping with the mutagenic role of ultraviolet radiation. Surprisingly, skin found to harbor p53 clones showed no clusters of Ki67 positive cells, unlike the situation for actinic keratoses or basal cell carcinomas. These results show that in human skin p53 mutation is not directly associated with genomic instability or abnormal cell cycling; that the p53 immunopositive clones are either genetically distinct or precursors to other squamous cell lesions of skin; and that p53 immunopositive clones are early lesions, in that gross disturbance of proliferation has not already occurred.