BACKGROUND: Nivolumab is approved for the treatment of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, the influence of the site of distant metastasis on the efficacy of immune checkpoint inhibitor in R/M HNSCC remains unclear. We investigated the prognosis of R/M HNSCC patients treated with nivolumab, focusing on the site of distant metastasis. METHODS: We reviewed the data of R/M HNSCC patients treated with nivolumab between April 2017 and June 2020 at Saitama Prefectural Cancer Center. The differences in the prognosis were evaluated according to the site of distant metastasis. RESULTS: Of the 41 patients enrolled, 26 (63.4%) had lung metastasis, 7 (17.1%) had bone metastasis, and 4 (9.8%) had liver metastasis. Ten patients (24.4%) had single-organ distant metastasis (lung metastasis in all cases). Univariate analysis identified lung metastasis alone (single-organ distant metastasis) was associated with a significantly better prognosis [HR0.37 (95% CI) 0.14-0.97 p = 0.04], while liver metastasis was associated with a significantly worse prognosis [HR3.86 (95% CI) 1.26-11.8 p = 0.02]. Multivariate analysis identified lung metastasis alone and liver metastasis as independent prognostic factors. While 7 patients (70%) with lung metastasis alone could be continued on nivolumab treatment or received subsequent chemotherapy, only 1 patient (25%) with liver metastasis received subsequent chemotherapy. CONCLUSION: The site of distant metastasis affects the prognosis of R/M HNSCC patients treated with nivolumab. Lung metastasis alone appears to be associated with a better prognosis, in that it allows easier transition to subsequent chemotherapy, while liver metastasis associates with a worse prognosis.