p53 is considered the guardian of the genome and as such has numerous functions. The TP53 gene is the most commonly mutated gene in cancer, and yet the exact biological significance of such mutations remains unclear. There are at least 12 different isoforms of p53, and the complexity of the p53 pathway may be in part related to these isoforms. Prior research has often not teased out what isoforms of p53 are being studied, and there is evidence in the literature that p53 isoforms are expressed differently. In this paper, we document the staining pattern of p53β isoforms in the skin and correlate it with mutational status in a subgroup of squamous proliferations of the skin. p53β isoforms are present in the cytoplasm of the differentiated layer of the epidermis and hair follicles (granular layer, infundibular and isthmus-catagen). p53β isoforms are diffusely expressed within the cytoplasm of well-differentiated squamous tumours with tetramerisation (C-terminal) domain mutations in TP53 Our results lend support to p53β isoforms being a marker of differentiation in keratinocytes.