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New triplet chemotherapy combinations are under investigation in advanced non small cell lung cancer (NSCLC). Carboplatin, plus paclitaxel, plus gemcitabine is among the most active and promising regimens. The use of more aggressive chemotherapy in order to improve results can increase toxicity. Amifostine (WR-2721) reduces toxicity of radiotherapy and chemotherapy and protects selectively a number of normal, but not neoplastic, tissue. Based on this background, we performed a phase II study on carboplatin, plus paclitaxel, plus gemcitabine with amifostine support in advanced NSCLC. Patients received chemotherapy at the following dosage: carboplatin AUC 5, i.v., at day 1; paclitaxel 175 mg/m2, i.v. by 3-hour infusion, at day 1; gemcitabine 1000 mg/m2, i.v. by 3-hour infusion, at days 1 and 8; every 3 weeks for a maximum of 6 cycles. Amifostine was administered at the dose of 740 mg/m2, i.v., at day 1 of each cycle. Seventeen patients entered the study. They were prevalently male, median age was 62 years, PS (ECOG) was 0 in 10 cases (58.8%), 1 in 6 (35.3%) and 2 in 1 (5.9%). Histology was epidermoid in 8 cases (47%) and adenocarcinoma in 9 (53%). We observed 8 (47.5%) objective responses with 2 (11.7%) complete responses. Median time to progression and median survival were 24 and 36 weeks, respectively. Treatment was well tolerated. The main toxicity was as follows: grade 3 neutropenia, grade 2 thrombocytopenia and grade 3 anemia in one (5.8%) case; grade 2 peripheral neurologic toxicity in 3 (17.6%) patients; grade 2 cardiac toxicity (atrial fibrillation) in one case; and grade 3 respiratory toxicity (dispnoea) in one patient. These data indicate that this combination has promising activity and tolerability. A randomized trial comparing carboplatin plus paclitaxel, plus gemcitabine versus carboplatin, plus paclitaxel, plus gemcitabine, plus amifostine in advanced NSCLC is warranted.