Esophageal squamous cell carcinoma (ESCC) has been reported to show geographical variation in its incidence, even within areas of ethnic homogeneity. Kashmir valley, in north of India, has been described as a high-risk area for ESCC. Here, we make a preliminary attempt to study mutations in exons 5–8 (the DNA binding domain) of the tumor suppressor gene, p53, in 55 ESCC patients from Kashmir. Polymerase chain reaction followed by direct sequencing analysis revealed the presence of mutations in 36.36% (20/55) tumors, assessed for the extent of allelic instability. The 20 mutations, found in 20 patients, comprised of 17 single-base substitutions (11 transitions + 6 transversions) and 3 deletions. The 17 single-base variations represented 12 missense mutations, 2 nonsense mutations and 3 variations located in intron 6, 1 of which resulted in a splicing variant. The patients when compared for the incidence of p53 mutation with various demographic features revealed females to be at increased risk (p = 0.016; OR = 4.13; 95% CI = 1.26–13.46). Comparison of mutation profile with other high-risk areas reflected both differences and similarities indicating coexposure to a unique set of risk factors. This might be due to the special dietary and cultural practices of Kashmir that needs validation, as does the gender-based difference in the incidence of p53 mutation observed in this study. © 2005 Wiley-Liss, Inc.