Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new treatments for metastatic melanoma (MM). We sought to determine the impact of these treatments in the ‘real world’. We took advantage of the Danish MM database (DAMMED), which contains data on the entire, unselected population diagnosed with MM within Denmark. All MM cases (excluding ocular MM, n = 837) diagnosed in three non-consecutive years marked by major changes in the first-line treatments (2012: interleukin-2 and BRAF inhibitors; 2014: anti–CTLA-4: Cytotoxic T-Lymphocyte Antigen 4 and 2016: anti–PD-1: programmed cell death protein 1 and MEK inhibitors) were retrieved. Patients were grouped into ‘trial-like’ and ‘trial-excluded’ based on the common trial eligibility criteria. In the ‘trial-like’ population (39% of all MM), the median overall survival (OS) was not reached in 2016 versus 18.8 months in 2014 (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.35–0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27–0.63; p < 0.0001). In the ‘trial-excluded’ population (61% of all MM), 75% had brain metastases and/or (performance status) PS ≥ 2. Here, the median OS improved to 6.9 months in 2016 versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52–0.84; p = 0.0008) and 4.2 months in 2012 (HR 0.66, 95% CI 0.52–0.84; p = 0.0007). Subgroup analysis of the BRAF wild-type population showed an improved 1-year survival rate in 2016 versus 2014 (35.9% vs 18.8%, p = 0.0153). In conclusion, the introduction of modern treatments has led to an improved survival of real-world patients with MM, regardless of their eligibility to clinical trials and the BRAF status. These data support the application of modern treatments to patient populations which are not represented in pivotal trials.