Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent malignancy worldwide. Immunotherapy with checkpoint inhibitors such as anti-CTLA-4 anti-PD-l and anti-PD-L1 has shown promising results in treating patients with recurrent/metastatic HNSCC. We aimed to systematically review the literature on immunotherapy with checkpoint inhibitors as treatment for advanced HNSCC. Methods: PubMed, EMBASE, Google Scholar, and the Cochrane Library were systematically searched with the purpose of identifying all studies addressing the effects of checkpoint inhibitors as treatment for HNSCC in human clinical trials. We assessed effects of the treatment with checkpoint inhibitors on overall survival (OS), progression-free survival (PFS), HPV-status, PD-L1-status, and adverse events. Results: We identified eight studies (n = 1431 patients) with an OS ranging from 7.5 to 14.9 months in PD-1 checkpoint inhibition. Two studies (n = 541 patients) observed a significantly (p = 0.01) and (p = 0.007) longer OS with checkpoint inhibition compared to standard-treatment, platinum-based chemotherapy (7.5 versus 5.1 months and 14.9 months versus 10.7 months). Two studies (n = 411 patients) found an increased OS associated with PD-L1-postive patients compared to PD-L1-negative patients. The eight studies have heterogenous design with only three being randomized. Conclusion: Few clinical trials have investigated the treatment with checkpoint inhibition for HNSCC. Solely, two randomized studies comprising 240 patients treated with nivolumab (anti-PD-L) and 301 patients treated with pembrolizumab (anti-PD-L) showed a significantly prolonged survival in patients with recurrent/metastatic HNSCC compared with standard-treatment. There is a further need for randomized clinical trials investigating a putative role of checkpoint inhibition in the treatment of advanced HNSCC.