Head and neck cancer and its treatment had a significant impact on the quality of life. EORTC QLQ-C30 and EORTC QLQ-H&N35 are the two most widely used modules to assess the quality of life among head and neck cancer patients. The aim of the study is to test the reliability and validity of Gujarati version of EORTC QLQ-C30 and QLQ-H&N35module in a clinical setting. Gujarati version of EORTC QLQ-C30 and QLQ-H&N35 was administered to 400 histo-pathologically proven cases of head and neck cancer. For testing the internal consistency (reliability) Cronbach’s alpha coefficient was used. The convergent and discriminant validity were explored by using Spearman’s correlation coefficient test. Factor analysis was performed to obtain information about loading of the items for each scale. All most all scales of EORTC QLQ-C30 and QLQ-H&N35 showed high internal consistency having Cronbach’s alpha coefficient > 0.70. Spearman’s correlation coefficient ranges from −0.45 to 0.95 for EORTC QLQ-C30 and 0.42–0.94 for EORTC QLQ-H&N35 showing moderate to good convergent validity. The magnitude of the correlation of each item with its own scale exceeded the correlation with another scale confirming item discriminant validity. The factor analysis resulted in 7 and 11 different components for measuring quality of life for EORTC QLQ-C30 and QLQ-H&N35 respectively. Based on the results obtained it can be concluded that the Gujarati version of both the modules is a reliable and valid tool for measuring quality of life in head and neck cancer patients in clinical settings.