Background: Clinical trials demonstrated a significantly improved recurrence-free survival (RFS) of melanoma patients treated adjuvantly with immune checkpoint inhibition (ICI) and targeted therapy (TT). As data from controlled trials are based on selected populations, we investigated melanoma patients with high risk of recurrence who opted for ICI, TT, or no adjuvant treatment (NoTx) under real-world conditions. Methods: In a prior analysis of this multicenter, retrospective cohort study, patients with resected melanoma stage III-IV between 06/2018 and 09/2019 were analyzed for adjuvant therapy choice (Lodde et al., Cancers 2021). In this follow-up study, the treatment course of ICI- and TT-treated patients as well as recurrence characteristics, subsequent management and outcomes also including NoTx patients were examined. Results: 814 patients were included (72 stage IIIA, 266 IIIB, 383 IIIC, 24 IIID, 69 IV; 309 BRAF mut); 533 patients received ICI (66%), 114 TT (14%, 36.9% of all BRAF mutated patients), 167 patients had opted for NoTx (21%). Median treatment duration was 10.2 and 11.7 months for ICI and TT, respectively. ICI was discontinued prematurely in 51% (273/533) and TT in 44% (50/114) of patients. The main reason for discontinuation was progressive disease (PD) in ICI patients (58%, 158/273) and adverse events in TT patients (60%, 33/50). At a median follow-up (FU) of 24.6 months for ICI, 25.3 months for TT, and 21.8 months for NoTx, 48% of ICI (255/533), 35% of TT (40/114), and 45% of NoTx (75/167) patients had developed a recurrence mostly at distant sites (ICI 62%, TT 63%, NoTx 64%). In patients with recurrence, median time from start of adjuvant treatment to 1^st recurrence was 6.1 months in ICI and 17.6 months in TT. Median RFS was 32.0 months for ICI (95% CI 25.7-38.3), not reached for TT, and 22.3 months for NoTx (95% CI 15.2-29.4). Among BRAF mut patients with stage III, risk of recurrence was higher for ICI than TT (hazard ratio adjusted for age, sex and tumor stage, 2.31; 95% CI 1.56-3.43). Subsequent systemic treatment for the 1^st recurrence was given in 76% (192/253) of ICI, 83% (33/40) of TT, and 53% (40/75) of NoTx patients. Among patients who received the 1^st subsequent systemic treatment for metastatic disease, PD was the best response in 67% (82/123) for ICI, 55% (11/20) for TT, and 50% (16/32) for NoTX. Conclusions: After 2 years of FU, recurrences were mostly at distant sites in all groups. ICI had higher discontinuation rates and more and earlier recurrences than TT. BRAF mut melanoma patients treated with ICI had a significantly higher risk of relapse than TT-treated patients. Response to subsequent systemic treatment was low for both ICI and TT.