The outcome of patients with stage IIIB/IV non-small-cell lung cancer treated with platinum-based chemotherapy as first-line therapy was investigated to determine if cisplatin- or carboplatin-based combination therapy have similar efficacy by comparing the overall survival and safety profile for each combination regimen. A total of 1,014 patients, treated for stage IIIB and IV NSCLC between January 2002 and December 2008, with initial ECOG performance status of 0 and 1, adequate hematologic, hepatic, and renal function, who received at least two cycles of third-generation platinum-based chemotherapy, survived greater than 90 days, and experienced death were included for survival and safety analysis. Of them, 788 patients received cisplatin-based chemotherapy and 226 carboplatin-based. Cisplatin-based regimen yield significant better overall survival with a median survival time of 324 days compared to that of the carboplatin-based regimen of 286 days, attributable to the survival benefit of patients with stage III B (379 days vs. 283 days, Log-rank P=0.003), or with histology of squamous (308 days vs. 262 days, Log-rank P=0.01). Patients of the carboplatin-based arm were more likely to experience thrombocytopenia (OR=0.560, 95% CI=0.332-0.944, P=0.028), while cisplatin-based chemotherapy was associated with more nausea and vomiting (OR=3.720, 95% CI=1.971-7.021, P<0.0001). Non-small-cell lung cancer patients with stage IIIB disease and good performance status have a better survival advantage when treated with third-generation cisplatin-based chemotherapy compared to carboplatin-based regimen, and patients with squamous histology type may have experienced greater survival benefit than those with adenocarcinoma.