Background: Cetuximab based regimen is the recommended palliative chemotherapy for head and neck squamous cell cancers. However, due to financial constraints, toxic intravenous chemotherapy with poor outcome is more commonly used in lesser developed countries. Retrospective studies have shown a role for oral metronomic therapy (MCT) in HNSCC especially in a resource poor setting. Methods: We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200 mg twice daily) and weekly methotrexate (15mg/m²)] to intravenous single agent cisplatin (IP) (75mg/m²) given 3 weekly. Patients with relapsed, metastatic and inoperable head and neck cancers meriting palliative chemotherapy,performance status 0-2, unaffordable for cetuximab and with adequate organ functions were eligible.. The primary end point was progression-free survival. The trial was powered to detect a 33% improvement in the median PFS, from 2.7 months for IP arm, with type 1 error of 5% and type 2 error of 80%. Univariate analysis of survival was performed using Kaplan Meier estimates with intention to treat analysis. Toxicity rates were compared using chi square test. Results: 110 patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (log-rank p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5 - 275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2 -199.8 days) (log-rank p=0.02). There were fewer grade 3/4 adverse effects wth MCT, which was nonsignificant.(18.9% vs. 31.4%, P = 0.14). Conclusions: Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting. It is a viable and cost-effective treatment option in patients not affording cetuximab. Further studies are warranted to evaluate the benefit, schedule and combination of metronomic therapy. Clinical trial information: 006359.