Background: Real-life data on health care costs and loss of productivity after implementing new agents for metastatic melanoma are important to supplement model-based economic data. Materials and methods: All patients registered in the Danish Metastatic Melanoma Database (DAMMED) and the National Patient Registry in 2007–2011 were compared to 2012–2016 after the implementation of checkpoint inhibitors and targeted therapy. Health care costs, social transfer income (STI), and loss of productivity were calculated with a 2-step one model generalised linear regression (GLM) model. Medicine costs were calculated separately. Results: In 2007–2011, 70 (15%) out of 464 patients were long-term survivors compared to 347 (32%) out of 1089 patients in 2012–2016. Total health care costs per patient year were significantly lower in the first treatment year (€41.457 versus €60.547, relative change (RC) 0.72, 95% confidence interval (CI) 0.56–0.94, p = 0.015) and without significant difference the second year in 2012–2016 compared to 2007–2011. Medicine costs per patient year increased the first (€85.464 versus €26.339, RC 3.39, 95% CI 2.61–4.41, p < 0.001) and the second (€26.464 versus €11.150, RC 2.59, 95% CI 1.98–3.40, p < 0.001) year in 2012–2016 compared to 2007–2011. Productivity increased for long-term survivors in 2012–2016 in contrast to 2007–2011. Conclusion: Implementation of targeted therapy and checkpoint-inhibitors has increased medicine costs more than three-fold for long-term survivors. Total health care costs excluding medicine costs were significantly lower for long-term survivors the first and without change the second treatment year in 2012–2016 compared to 2007–2011. However, the number of treated patients increased which leads to an increase in overall total health care costs. Importantly, productivity increased for long-term survivors in 2012–2016.