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Matuzumab is a humanized IgG1 EGFR monoclonal antibody. This phase I study investigated the tolerability, safety and pharmacokinetics (PK) of matuzumab in combination with paclitaxel in patients with EGFR-expressing advanced non-small cell lung cancer (NSCLC). Six dose levels/schedules of matuzumab were explored in combination with paclitaxel. Dose was escalated from 100 mg to 1,600 mg on a modified Fibonacci scheme according to the incidence of dose-limiting toxicity (DLT) over the first two cycles. DLT was assessed in patients who completed the first two treatment cycles or who stopped treatment because of a DLT during those cycles. Patients with non-progressive disease could then continue to receive study treatment for up to 6 months. The safety population comprised 44 patients, with DLT evaluable in 33. The maximum tolerated dose was not reached, with only one DLT reported at the 1,600 mg 3-weekly dose level. The most frequent grade 3/4 adverse events across all cycles were dyspnea (23 %) and neutropenia (11 %). Matuzumab exhibited non-linear PK, with accumulation after escalation and repeated dosing. Tumor growth control was seen in 15/44 (34 %) patients, including 5/9 (56 %) at the 800 mg weekly dose level. Matuzumab combined with paclitaxel was generally well tolerated in patients with advanced NSCLC. There was some evidence of anticancer activity in relation to the matuzumab 800 mg weekly dose.