BACKGROUND: It was reported that treatment outcomes of the salvage chemotherapy (SCT) following nivolumab are fairly good compared with those of nivolumab itself. However, predictive factors of SCT for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) were not determined. METHODS: Twenty-one R/M HNSCC patients received SCT following nivolumab. The treatment outcome and predictive factors for the favorable response to SCT were investigated. RESULTS: The objective response rate (ORR) and the disease control rate of SCT were 52.4% and 81.0%, respectively. The median progression-free survival and the median overall survival time were 5.4 and 12.9 months, respectively. Patients with positive programmed death-ligand 1 (PD-L1) expression showed greater tumor shrinkage evaluated by the response evaluation criteria in solid tumors and higher ORR than those with negative PD-L1 expression. CONCLUSIONS: Treatment outcome of SCT following nivolumab in R/M HNSCC was favorable. PD-L1 expression may be a predictive factor of SCT.