Background: The efficacy of epidermal growth factor receptor (EGFR) inhibitors has been demonstrated in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC). However, dermatological reactions to these inhibitors can cause significant physical and psycho-social discomfort to patients. The objective of the present study was to evaluate the efficacy of EGF ointment on EGFR inhibitor-related skin adverse events (ERSEs). Methods: This placebo-controlled, double blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC who were treated with EGFR inhibitors. Only patients with grade ≥ 2 ERSEs according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v. 4.0 were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. EGF ointment was evenly applied to skin lesions twice daily. The response of study treatment was defined as follows: (1) improvement of ERSEs from grade ≥ 2 to grade ≤ 1, or (2) grade 3 or 4 ERSEs downgraded to grade 2 and lasted for at least two weeks. Quality of life (QoL) was evaluated with SKINDEX-16. Results: Between June 2015 and September 2017, 90 patients were enrolled in eleven institutes. Final efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3 (P = 0.042). There was a linear correlation between different EGF concentrations and responses (P = 0.012). QoL was assessed in 74 patients. Results of SKINDEX-16 were analyzed as three domains’ (symptoms, emotions, and functioning) scores and a composite score. Maximum changes in composite scores after treatment were significantly different among arms (mean ± standard deviation: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and -18.6 ± 17.7 for arm 3; P = 0.008). EGF arms (arms 1 and 2) showed significant improvement in emotions (P = 0.005) and functioning (P = 0.044) scores than the placebo arm. Conclusions: EGF ointment is effective for managing ERSEs and also improves patients’ QoL compared to placebo. (NCT02284139). Clinical Trial Number: The study was registered at ClinicalTrials.gov (NCT02284139). Funding Statement: This study was supported by Daewoong Pharmaceutical Company and Dong-A university research fund. Declaration of Interests: Conflict of interest relevant to this article was not reported. Ethics Approval Statement: This study was performed in accordance with the Declaration of Helsinki. It was approved by Institutional Review Boards or independent ethics committees of all investigational sites.