We aimed to evaluate, in a phase II study, the efficacy of the mitomycin-vinorelbine combination in non-small cell lung cancer (NSCLC) patients, relapsing after taxane-based regimens, a situation in which no standard chemotherapy is currently available. Patients with NSCLC progressing or relapsing after taxane therapy, with a Karnofsky performance status 50-100, and without clinical or biological contra-indications, were given mitomycin (8 mg/m(2) day 1) plus vinorelbine (25mg/m(2) days 1 and 8) every 3 weeks. Responses were assessed every three cycles. Sixty-five eligible patients were registered between December 2000 and December 2005. Taxanes and cisplatin were previously administered in 100% and 88% of the patients, respectively. All but four received at least two previous chemotherapy regimens. Two hundred and twenty-two cycles of chemotherapy were administered. The main grade 3-4 toxicity was leucopenia, in 47% of the patients. Among 60 assessable patients, response rate was 10% (95% confidence interval [CI]: 4-21). Median progression-free survival (PFS) was 9.7 weeks (95% CI: 8.4-11.1) and median survival (MST) was 28.4 weeks (95% CI: 23.0-34.8). Patients always progressing on all chemotherapy regimens administered before mitomycin-vinorelbine (primary failures) had shorter median PFS (8.1 weeks) than those having at least once partial response (PR) or no change (NC) (secondary failures) (10.4 weeks) (p=0.02). Respective MST were 23.7 weeks and 29.3 weeks (p=0.16). In conclusion, mitomycin-vinorelbine combination is a moderately active regimen in heavily pre-treated patients with NSCLC relapsing or progressing after taxanes and platinum-based chemotherapy. Its toxicity is limited.