Kangri cancer is a unique, thermally induced squamous cell carcinoma (SCC) of the skin that develops due to persistent use of a Kangri (a brazier) by the Kashmiri people to combat the cold temperature during winter. Unlike classical UV-induced SCC of the skin, Kangri cancer appears on the legs and abdomen. Its common features are erythematous patches, recurrence and metastasis. In the absence of any molecular etiology, we made a preliminary attempt to estimate the nature and frequency of mutations in the TP53 and PTEN genes in Kangri cancer patients from Kashmir. PCR-SSCP analysis followed by direct sequencing revealed that TP53 mutations account for 40% (12/30) of sporadic Kangri cancer patients and that PTEN mutations account for only 6.6% (2/30). There were 16 mutations in TP53 exons 5 and 7, found in 12 patients. They consisted of 11 substitutions (7 transitions, 3 transversions and 1 double-base) and 5 insertions. The 11 substitutions represent 8 distinct missense mutations, 3 of which were silent mutations. The mutations detected in the PTEN gene consisted of one insertion and one C>T transition. This high percentage of TP53 mutations (especially A>G) showed a statistically significant association with age and positive lymph node status. Our results indicate that TP53 is a predominant target of chronic hyperthermia in the development of Kangri cancer in the moderate risk Kashmiri population. The differences in the TP53 mutation spectrum of UV-induced SCC of the skin and Kangri cancer are probably due to the nature of the respective environmental carcinogens. The study also suggests that TP53 may function as a potential molecular marker and prognostic tool, at least in a subset of sporadic Kangri tumors.