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Background: The survival in metastatic melanoma has dramatically improved after the introduction of immune checkpoint‐ (ICIs) and MAPKinase inhibitors (MAPKis). Objective: Our aim was to describe therapy response and survival in a real‐world population as well as to assess the associations between clinical variables and therapy outcome for patients with metastatic melanoma receiving first‐line ICIs or MAPKis. Methods: A total of 252 patients with metastatic (stage IV) melanoma were prospectively followed between 1 January 2010 and 3 December 2017 with follow‐up until 31 March 2019, at the Karolinska University Hospital, Sweden. Hazard ratios (HRs) for progression‐free survival (PFS) and overall survival (OS) were analysed with Cox regression, and logistic regression was used to estimate odds ratios (ORs) for therapy response. Results: Patients receiving ICIs (n = 138) experienced longer PFS compared to patients that received MAPKis (n = 114; median PFS for ICIs was 6.8 months, and median PFS for MAPKis was 5.3 months). In the multivariable analyses of clinical markers, increasing M‐stage (OR 0.65; 95% CI 0.45–0.94; P = 0.022) and male sex (OR 0.41; 95% CI 0.19–0.90; P = 0.027) were significantly associated with lower response to ICIs. Lower baseline albumin levels (OR 0.90; 95% CI 0.83–0.98; P = 0.019) and male sex (OR 0.33; 95% CI 0.12–0.93; P = 0.036) were related with lower response to MAPKis. For ICIs, increasing M‐stage (HR 1.34; 95% CI 1.07–1.68; P = 0.010), increasing LDH (HR 1.73; 95% CI 1.19–2.50; P = 0.004) and decreasing albumin (HR 1.06; 95% CI 1.01–1.10; P = 0.011) were significantly associated lower PFS in the adjusted model. The corresponding markers for MAPKis were increasing LDH (HR 1.44; 95% CI 1.08–1.92; P = 0.013) and decreasing albumin (HR 1.05; 95% CI 1.02–1.09; P = 0.005) for PFS. Conclusion: ICIs and MAPKis were effective in this real‐world population, and we could confirm the importance of previously reported clinical prognostic markers. Albumin values may be associated with therapy outcome but need further validation. [ABSTRACT FROM AUTHOR]