BACKGROUND : Eruptive squamous atypia (ESA), which is an idiopathic, sometimes koebnerizing, proliferation of atypical but well-differentiated keratinocytes (also termed eruptive keratoacanthoma), is often misdiagnosed as cancer and managed by excisional surgery, provoking further koebnerization. A clear definition of this phenomenon and treatment outcome data are lacking. OBJECTIVE : To define ESA and evaluate efficacy of intralesional (IL) 5-fluorouracil (5-FU) treatment. METHODS : A retrospective cohort study examined patients with ESA that arose spontaneously or within a recent surgical scar and was treated with IL 5-FU at a tertiary academic center between January 2008 and December 2016. Complete clearance, partial clearance, and number of surgical excisions performed were tabulated. RESULTS : Of 30 patients with 136 ESA lesions, 20 (67%) had resolution of ESA with IL 5-FU monotherapy. In all, 10 patients (33%) required additional therapy (topical 5-FU, steroids, cryotherapy, or acitretin). No IL 5-FU-treated ESA lesions required surgical excision. The number of excisional procedures decreased significantly (P = .006), with 27 patients (90%) needing fewer excisions 12 months after versus 12 months before initiation of IL 5-FU therapy. Dyspigmentation was the only adverse event. CONCLUSIONS : Limitations include retrospective analysis and use of data from a single institution. CONCLUSIONS : With close clinical monitoring, IL 5-FU can be used to successfully treat ESA.