Background: Platinum-based doublet chemotherapy is the standard chemotherapy regimen for treatment-naïve advanced Non-Small-Cell Lung Cancer (NSCLC). S-1, an oral fluoropyrimidine, combined with carboplatin or cisplatin (CDDP) has shown no less efficacy than standard platinum doublet chemotherapy in Japanese NSCLC patients. However, the effectiveness in Chinese NSCLC patients is uncertain. We aimed to compare the efficacy and safety of these chemotherapy regimens in Chinese NSCLC patients. Methods: In this study, we recruited patients aged 18-70 years with stage IIIB, IV or recurrence, histologically or cytologically confirmed NSCLC, ECOG performance status of 0-1, have at least one measurable lesion, and adequate organ function. Patients were randomized in 1:1 ratio to receive either S-1 (80–120 mg/day, PO, BID, days 1 to 21) with 60 mg/m² CDDP on day 8 every 5 weeks (SP) or docetaxel and CDDP (both 75 mg/m²) on day 1 every 3 weeks (DP), for up to 6 cycles. The primary endpoint was progression-free survival (PFS) and all CT scans were extramurally reviewed by Independent Review Committee (IRC). Non-inferiority study design was employed as upper confidence interval (CI) limit for hazard ratio (HR) < 1.33. Results: Between March 2011 and November 2012, 246 patients from 21 institutions in China were randomly assigned and received SP or DP treatment (124 vs 122) with 18-month follow-up period from the last patient randomized. In the SP and DP group, median PFS was 5.9 and 5.7 months (HR = 0.68; 95% CI, 0.48 to 0.96) respectively, median overall survival was 19.1 and 14.8 months, respectively (HR = 0.84; 95% CI, 0.61 to 1.14). The most common grade 3 or worse adverse events in both treatment groups were neutropenia 3.3% vs 55.1%, leukopenia 1.7% vs 39.0%, and febrile neutropenia 0.8% vs 5.9%, of 121 patients in the SP group and of 118 patients in the DP group, respectively. Conclusions: The efficacy of SP was non-inferior to DP. Well-tolerated safety could be provided by SP regimen. SP would be a new first-line chemotherapy regimen for Chinese patients with advanced NSCLC. Clinical trial information: Japic CTI-111479.