Background: The efficacy of ICIs in metastatic melanoma is well-established. However, there is limited data regarding their efficacy in in-transit melanoma metastases (ITM). This study assessed the efficacy of ICI in patients with ITM. Methods: A multisite, retrospective review of patients with ITM treated with ICI from 2004-2018. Demographic and clinicopathological factors (age, sex, primary site, AJCC version 8 stage, BRAF status, prior locoregional therapies) were collected. Objective response rate (ORR) based on a clinician-assessed best overall response, progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Results: Fifty-four patients were included: 27 (50%) female; median age 69 (range 19-89); 12 (22%) stage IIIB, 40 (74%) stage IIIC and 2 (4%) stage IIID; 10(19%) BRAF mutant. Forty (74%) received single agent PD-1 inhibitor (pembrolizumab or nivolumab), 8 (15%) single agent anti-CTLA-4 (ipilimumab), 5 (9%) combination anti-PD-1/anti-CTLA-4 (ipilimumab and nivolumab or pembrolizumab) and 1 (2%) combination anti-PDL-1/MEK inhibitor (atezolizumab and cobimetinib). ORR to ICI was 54%: 14 (26%) complete responses; 15 (28%) partial responses; 9 (17%) stable disease; 16 (30%) progressive disease. Thirteen (46%) responders had only one ITM lesion. ORR was 58% for single agent anti PD-1, 38% for single agent anti-CTLA4, and 40% for anti-PD-1/anti-CTLA-4 (Table). The median follow-up was 15 months (2-46). The median PFS was 11.7 months (6.6-N/A). PFS at 1 and 2 years were 48% and 39%. Fourteen (56%) progressed locoregionally and 11 (44%) progressed distantly. OS at 1 and 2 years were 85% and 63%; the median OS was not reached. No clinicopathological features were associated with ORR. Conclusions: ICI produces objective responses in ITM and should be considered in patients with unresectable ITM or disease recurrence despite locoregional therapies.