Background: Prevalence of HPV in oropharyngeal squamous cell carcinomas is well documented however few studies had evaluated it in pyriform fossa. This study was aimed to evaluate expression of p16 in squamous cell carcinomas of pyriform fossa as compared to oropharynx and oral cavity. Methods: 148 cases of squamous cell carcinomas of head and neck diagnosedonly on biopsies were evaluated for p16 and p53 expression in tertiary care centre.Correlation with demographic parameters andhistological grade performed. Results: In overall, p16 was positive in 67 cases (45.27%) and p53 in 109 cases (73.7%). p16 was positive in 17 /36 cases in pyriform fossa (47.22%), 47/62 cases in in oropharynx (70.1%) and 3/50 in oral cavity (4.47 %). p53 was positive in 30/36 cases in pyriform fossa (83.33%), 34/62 cases in oropharynx (54.83%) and 45/50 cases in oral cavity (90%). Mean age was 60.61yearsand medianof 62 years. M:F ratio was 6:1. Well differentiated SCCs showed maximal p53 positivity whilemoderately and poorly differentiated SCCs showedmixed p16 and p53. 11/25 (44%) MDSCC K and 5 out 6 MDSCC-NK cases in pyriform fossa expressed p16 while 20/ 25(80%) MDSCC Kand 6/6 MDSCC NKcases in pyriform fossa were p53 positive,Significant association of p16was found with tumour site, grade, and smoking (p value <0.05) but not with age, gender,and alcohol. Conclusions: Squamous cell carcinoma of pyriform fossa expressedp16 significantlyas compared to those in oropharynx. p53 expression is a constant finding at all sites.