Background: The efficacy of the EGFR inhibitors has been demonstrated in non-small cell lung cancer (NSCLC), pancreatic cancer (PC) and colorectal cancer (CRC). Dermatological reactions can cause significant physical and psycho-social discomfort to patients. In present study, we evaluated the efficacy of EGF ointment on EGFR inhibitor related skin side effects (ERSEs) Methods: this was placebo-controlled double blind, multicenter, phase III trial. The patients diagnosed as NSCLC, PC, or CRC who were treated with EGFR inhibitors (e.g. erlotinib, gefitinib, cetuximab). Only patients with Grade ≥2 ERSEs according to the NCI-CTCAE v. 4.03 were enrolled. The patients were randomized to 3 groups; A (placebo) group, B (1ppm concentration of EGF ointment), or C (20ppm of EGF ointment). The response to study drug was defined as follows: (1) Grade 2, 3, or 4 ERSEs downgraded to ≤Grade 1 or (2) Grade 3 or 4 ERSEs downgraded to Grade 2 and persisting for at least two weeks. The quality of life (QoL) was evaluated with SKINDEX-16. Results: Between Jun 2015 and Sep 2017, final efficacy evaluation included 80 patients. Palmar plantar erythrodysesthesia was main symptomatic ERSEs of PC, Rash/Acne was main symptomatic ERSEs of NSCLC and CRC. According to the definition of effectiveness, response to EGF study drug of A (placebo), B (1ppm), or C (20ppm) were 44.4%, 61.5%, and 77.8%, respectively (P= 0.0424). They had been observed linear correlation between different EGF concentration groups (P= 0.0119). The QoL results of the SKINDEX-16 were analyzed as an overall score and three domain scores (including symptoms, emotions and functioning), and reported as mean value. Mean ± standard deviation (SD) score change from baseline to maximum response of A (placebo), B (1ppm), or C (20ppm) were -5.16 ± 8.62, -11.74 ± 14.16, and -18.58 ± 17.70, respectively (P= 0.0078). Comparing with placebo group, emotions (P= 0.005) and functions (P= 0.044) score domains were much improved by EGF containing group. Conclusions: Based on the results, the EGF ointment is effective for ERSEs compared with placebo. The EGF ointment evenly improved all kinds of symptoms and QoL of patients with ERSEs. Clinical trial information: NCT02284139