Objective The aim of this study was to investigate if the treatment outcomes of checkpoint inhibitors (CPI) in patients with advanced-stage skin head and neck melanoma (HNM) differs from outcomes in patients with non-HNM. Design A retrospective cohort study of patients with unresectable AJCC stage III and stage IV, who received CPI between 2010 and 2017. Participants Overall, 122 unresectable AJCC stage III and metastatic stage IV melanoma adult patients were treated with CPI during the study period (consecutive patients). The HNM group of patients was comparable with limbs and trunk melanoma group except different distant metastatic (M1a/b/c/d) pattern (p = 0.025). Main outcomes Comparison of overall survival and clinical response to CPI in patients with advanced-stage skin melanoma of the head and neck with non-HNM. Results We analyzed 38 patients with melanoma arising in the head and neck skin regions, 33 with melanoma of limbs and 51 with trunk melanoma. Most of the head and neck patients were men (89.5%), the average age of melanoma diagnosis was 61.4±16.7 years (range 16.4- 85.6). More than a third of HNM group of patients (36.8%) were 70 years and older. Overall response rate (ORR) to CPI was 50% (CR 31.6% and PR 18.4%) in the head and neck study group of patients, compared to an ORR of 36.3% and 23.5% in melanoma of the limbs and of the trunk, respectively (p = 0.03). The median overall survival of HNM group of patients was 60.2±6.3 months, CI 95% [47.7-72.7], 63% were alive at 30 months, reaching a plateau. Whereas, the median survival time of limbs and trunk melanoma were 51.2 and 53.4 months, which did not reach significance. Conclusions and relevance Response rate to CPI is significantly improved in patients with melanoma of the head and neck and they have a trend towards improved, long standing, overall survival.