Summary Background The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov , number NCT00148798. Findings 518 patients in the chemotherapy plus cetuximab group—290 of whom had first-cycle rash—and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months 95% CI 12·8–16·4 vs 8·8 months 7·6–11·1; hazard ratio HR 0·631 0·515–0·774; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months 5·2–5·7 vs 4·3 months 4·1–5·3; HR 0·741 0·607–0·905; p=0·0031) and response (rate 44·8% 39·0–50·8 vs 32·0% 26·0–38·5; odds ratio 1·703 1·186–2·448; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months 7·6–11·1 vs 10·3 months 9·6–11·3; HR 1·085 0·910–1·293; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, 14·1–20·6 vs 9·3 months 7·7–13·2; HR 0·614 0·453–0·832; p=0·0015), squamous-cell carcinoma (median 13·2 months 10·6–16·0 vs 8·1 months 6·7–12·6; HR 0·659 0·472–0·921; p=0·014), and carcinomas of other histology (median 12·6 months 9·2–16·4 vs 6·9 months 5·2–11·0; HR 0·616 0·392–0·966; p=0·033). Interpretation First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding Merck KGaA.