8034 Background: Paclitaxel + gemcitabine + cisplatin showed promising results in phase II with 59% response rate and 48 weeks median survival. Hence, it was compared to a standard doublet regimen to examine for superiority. Methods: Histologically verified inoperable NSCLC patients (pts) aged 18–75 years, performance status 0–2 and normal organ function were randomized to regimen A (paclitaxel 180 mg/m2 and cisplatin 100 mg/m2 day 1 with gemcitabine 1000 mg/m2 day 1 and 8 every 3 weeks) or regimen B (cisplatin 100 mg/m2 day 1 and weekly i.v. vinorelbine every 4 weeks) for maximum 6 cycles. Totally 428 pts were needed to detect a 30% median survival increase with 80% power and two-sided type 1-error of 5%. Results: 221 pts.received reg. A and 222 reg. B. Overall, median age was 62 years (range 38–75 yrs), 58% were males, 11% had performance status 2, 62% stage IV disease, 46% adenocarcinoma, and 28% squamous cell carcinoma (SCC), equally distributed between the regimens. Median no. of treatment courses were 4 in both regimens. Frequencies of CTC grade 4 leucocytopenia, thrombocytopenia, or grade 3+4 nausea, neurotoxicity, or nephrotoxicity were 15%, 17%, 19%, 8%, and 8% in reg. A, and 18%, 5% (p=0.001), 17%, 11%(p=0.014), and 7% in reg. B, respectively. Febrile leucopenia episodes were 14% and 10% in reg. A and B, while thrombocytopenic bleedings occurred in 12% and 4% of pts (p=0.008), respectively, with two toxic deaths due to bleeding in reg. A and none in reg. B. Response rates were 52% and 49% in reg. A and reg. B, median response durations were 263 and 217 days (not significant), median times to progressions (TTP) 6.7 and 5.8 months (p=0.453), and median survival times 11.4 and 10.8 months (p=0.415), respectively. In SCC subtype, TTP was higher in reg. A than reg. B (medians 7.0 mths vs. 4.1 mths, p=0.001) and survival was increased (medians 13.5 mths vs 9.7 mths, p=0.020). Conclusions: The triplet regimen A had significantly higher activity in SCC, both with respect to TTP and to survival with median survival in excess of one year and may be preferred in this histologic subtype. [Table: see text]