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Background: Head-and-neck squamous cell cancers (HNSCC) are common in India. Recurrent and metastatic HNSCC carry a poor prognosis. The chemotherapy options are limited, and the median survival is measured in months. The addition of targeted antibodies and immunotherapy improves overall survival (OS). In resource-limited settings, chemotherapy remains the only option in advanced HNSCC. Objectives: We aimed to assess the efficacy and safety of the combination of paclitaxel and Mycidac-C (heat-killed Mycobacterium w) in the palliative setting for advanced HNSCC. Materials and Methods: This was a retrospective study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India in patients with relapsed/refractory or metastatic HNSCC who received the combination of paclitaxel and Mycidac-C between August 2019 and May 2020. Patients were treated until progression or unacceptable toxicity. The study was approved by the Institutional Ethics Committee, and the requirement for written informed consent was waived. Results: We included 28 patients in the study. Most of the patients (22, 78.6%) had oral cavity cancers and had platinum-refractory disease (25 patients, 96.4%). The median age was 51 years (range, 31-70), 26 (92.9%) patients were male, and 25 (89.3%) had a performance status of 0-1. At least two lines of previous therapies had been administered to 23 (82.1%) patients. The median duration of follow-up was 3.4 months (range, 0.2-18.1). The median numbers of cycles of paclitaxel and Mycidac-C administered were 3 (range, 1-6) and 2.5 (range, 1-6), respectively. The median progression-free survival (PFS) and OS were 2.9 months (95% confidence interval [CI], 2.36-3.48) and 4.9 months (95% CI, 3.78-5.99), respectively. The most common adverse effects were anemia in 26 (93.9%) patients and increased alanine aminotransferase and aspartate aminotransferase levels in five (17.9%) and four (14.3%) patients, respectively. Four (14.3%) patients developed neutropenia, two (7.1%) developed diarrhea, and two (7.1%) developed peripheral neuropathy. Conclusion: In resource-limited settings, the combination of paclitaxel and Mycidac-C can be considered a therapeutic option for patients with advanced relapsed/metastatic HNSCC.