Objective. The aim of this study was to measure quality of life (QOL) in patients with upper aerodigestive tract (UADT) cancer in comparison with hospital-based controls. We also assessed the impact of various clinical predictors at time of diagnosis of disease/cancer on QOL in these patients. Study Design. A case-control study was conducted (N ¼ 480) with 240 UADT cancer cases and 240 controls matched by gender and age (5 years) from 2 different hospitals in Pune, India. The University of Washington Quality of Life Questionnaire was used to measure QOL and was administered through face-to-face interviews. Various QOL domains were analyzed by using one-way analysis of variance and Bonferroni adjustments for post hoc comparisons. Results. Cases had significantly lower scores across all domains of QOL compared with controls. Overall, the most affected domains were anxiety and mood. Cancer site significantly influenced QOL, with patients with cancers of the oropharynx and hypopharynx having the worst mean scores across all domains. Patients with stage IV cancer had the worst mean scores across the majority of the QOL domains. Our findings highlight the complex interactions between individual and clinical predictors that have an impact on QOL. Conclusions. QOL needs to be incorporated as an important outcome measure in an individualized approach to therapeutic and palliative care planning to enable a better quality of survival of patients with UADT cancers.