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Background: Reliable evidence to guide the management of melanoma in situ (MIS) and minimize the risk of recurrence is lacking. Objective: To identify clinicopathological predictors of local recurrence (LR) in patients with MIS and evaluate long-term outcomes according to pathological excision margins. Methods: A case-control study of patients with MIS treated at a large Australian melanoma treatment center from January 2008 to December 2012 was undertaken. Clinicopathological characteristics of patients who developed LR and those who did not were compared. Results: LR developed in 34 of 1407 patients with MIS (2.5%). Median time to LR was 20 months. The primary lesion was removed with pathological margins <4 mm (P < .001) in 67.6 % of patients with LR. Four patients died of metastatic melanoma following LR. Comparing patients with pathological margins <4 mm and ≥4 mm, the former were older (>60y, P < .001), more frequently had MIS on the head or neck (P < .001), had a greater LR rate (P < .001), and had a higher mortality from all causes (P < .001). Limitations: Retrospective, single-institution study. Conclusions: Pathological margins of ≥4 mm should be considered for patients with MIS who are treated with standard surgical excision and assessed by examining serial slices taken from the formalin-fixed, paraffin-embedded specimen.