Background: The ability to analyze tumor mutation profiles has altered the oncology treatment landscape over the past decades. However, little is known about the effect of specific gene mutations on the response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: All unresectable stage IIIc and IV patients with BRAF V600, NRAS mutations and BRAF and NRAS wild-type patients treated with anti-PD-1 or ipilimumab-nivolumab between 2012 and 2020 were included from the Dutch Melanoma Treatment Registry, a nationwide population-based registry. Outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A Cox model was used to analyze the association of possible prognostic factors with PFS and OS. Results: In total 1358 first-line patients treated with anti-PD-1 and 524 treated with ipilimumab-nivolumab were included. Median follow-up was 25.6 months for anti-PD-1 treated patients and 16.3 months for ipilimumab-nivolumab treated patients. The highest ORR, in first-line, to anti-PD-1 was in patients who were BRAF and NRAS wildtype (50.2%), compared to BRAF V600 (43.8%) and NRAS mutated patients (49.8%). ORR to ipilimumab-nivolumab was highest in NRAS mutated patients (44.9%), while ORR was 39.5% for BRAF mutated patients and 40.3% for wild-type patients. Median PFS in the anti-PD-1 treatment regimen was significantly higher (p = 0.049) for double wild-type patients (16.7 months) patients than for BRAF mutated patients (9.9 months) and NRAS mutated patients (11.3 months). PFS was not significantly different (p = 0.11) in the ipilimumab-nivolumab treatment cohort, with a median PFS of 6.5 months for the wild-type group, 10.8 months for the BRAF group, and 9.1 months for the NRAS group. In the anti-PD-1 treated patients, median OS was significantly higher (p < 0.001) for BRAF mutated patients (32.8 months) compared to NRAS (21.0 months) and wild-type patients (23.0 months). For ipilimumab-nivolumab treated patients, median OS was also significantly higher (p < 0.001) for BRAF mutated patients (36.5 months) than for NRAS mutated patients (11.8 months) and wild-type patients (16.1 months). After adjustment for potential confounders, the presence of a BRAF mutation remained associated with lower PFS in the anti-PD-1 treatment cohort and better OS in both treatment cohorts. Higher age, higher ECOG score, elevated LDH levels, liver metastases and brain metastases were associated with worse survival. Conclusions: PFS in first-line PD-1 was significantly higher for double wild-type patients than for BRAF mutant and NRAS mutant patients. PFS in ipilimumab-nivolumab treated patients did not significantly differ between BRAF mutant, NRAS mutant and double wild-type patients. OS was significantly higher for BRAF mutant patients in both treatment strata, which is probably the result of the subsequent BRAF/MEK-inhibition treatment option in this group.