OBJECTIVES: Evaluate changes in health related quality of life (HRQoL) in patients with metastatic head and neck cancer randomized to receive either metronomic (methotrexate and celecoxib) or cisplatin chemotherapy. METHODS: Patients older than 18 years, Karnofsky performance score of > 70 and diagnosed with metastatic, locally advanced inoperable or recurrent head and neck cancer not amenable to surgery or radiation were randomized (1:1) to receive of metronomic or 6 cycles of cisplatin chemotherapy. All patients were recruited from the Tata Memorial Hospital (TMH), Mumbai, India. In addition to demographic and baseline clinical characteristics, patients were asked to rate their HRQoL using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35 questionnaires (Indian versions) at baseline and at the end of each chemo-cycle (every three weeks) till the end of study (week 18) or early termination. RESULTS: Of the 110 patients screened, 87 agreed to participate in the study. Mean age of the study population was 47.5 years (S.D.± 10.04) for the metronomic group and 47.2 years (S.D.± 9.89) for the cisplatin group. Oral cavity was the primary site of cancer (metronomic arm: 77.8%; cisplatin arm: 71.4%). About 57.8% and 45.2% patients had a history of tobacco use in both treatment arms. Overall quality of life was not significantly different between the two treatment groups from baseline to end of treatment. However, there was a statistically significant improvement in Pain QLQ-C30 score from baseline to week 3 (OR=3.14, p=0.036) and week 6 (OR=3.33, p=0.034) in the metronomic arm compared with the cisplastin arm. CONCLUSIONS: Understanding the impact of different treatment options on changes in QoL over time can not only aid physicians in communication with patients but also assist in the design of interventions that focus on rehabilitation of patients with head and neck cancer.