BACKGROUND: Despite durable responses achieved with Immune Checkpoint Inhibitors (ICIs), data about optimal duration of treatment, especially in the context of adverse events, remain scarce. OBJECTIVE: To systematically review the evidence concerning the impact of treatment discontinuation with ICIs for reasons other than progressive disease (PD) on relapse rates and survival of melanoma patients. METHODS: A systematic literature search was conducted in three electronic databases until July 2024. Studies referring to melanoma patients who ceased ICIs electively (i.e. due to complete response (CR), protocol completion or patient/physician's wish) or due to treatment-limiting toxicities (TLTs) were selected. Relapse rates (RRs) post cessation, time to PD, rechallenge and disease control rate (DCR) after 2 RESULTS: 38 and 35 studies were included in qualitative and quantitative synthesis, respectively. From 2542 patients discontinued treatment with ICIs electively or due to TLTs, 495 experienced progression [number of studies (n)=34, RR 20.9%, 95%CI 17.1 - 24.7%, I CONCLUSION: Discontinuation of ICIs in patients without progression is possible. Outcomes to rechallenge with ICIs may differ depending on the reason for discontinuation, but remains a considerable option. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42024547792.