Background: Locally advanced head and neck cancer treated with radical chemoradiation have unsatisfactory outcomes. Oral metronomic chemotherapy improves outcomes in comparison to maximum tolerated dose chemotherapy in the palliative setting. There is also limited evidence that it may do so in an adjuvant setting. Hence this randomised study was conducted. Methods: Patients of HN cancer with primary in oropharynx, larynx or hypopharynx, with PS 0-2 post radical chemoradiation with documented complete response were 1:1 randomised to either observation or oral metronomic adjuvant chemotherapy (MAC) for 18 months. MAC consisted of weekly oral methotrexate (15 mg/m2) and celecoxib (200 mg PO BD). The primary endpoint was OS and the overall sample size was 1038. The study had 3 planned interim analyses for efficacy and futility. Results: 137 patients were recruited and an interim analysis was done. The 3 year PFS in the observation arm was 67.1% (95% CI 53.8-77.3) and the same in the MAC arm was 62.5%(95%CI 49.4-73.1). The corresponding hazard ratio was 1.402 (95% CI 0.7393-2.66, P-value = 0.3). The 3 year OS in the observation arm was 77.3% (95% CI 64.4-86) and the same in the MAC arm was 64.1% (95%CI 51-74.5). The corresponding hazard ratio was 1.588 (95% CI 0.8734-2.886, P-value = 0.1). Any grade mucositis was seen in 30 patients (45.5%) in the MAC arm and 20 patients (28.2%) in the observation arm (P-value = 0.05). The rate of grade 3 or above mucositis was 7.6%(n = 5) in the MAC arm and 1.4%(n = 1) in the observation arm (P-value = 0.106). Conclusions: Both arms had similar OS. Hence observation post complete response post radical chemoradiation remains the standard of care. Clinical trial information: CTRI/2016/09/007315.