Background: Real-world evidence lacks for clinical effectiveness and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) in Chinese patients. Methods: Patients receiving first-line chemotherapy for advNS-NSCLC in four Chinese tertiary care hospitals from 2007 to 2012 were retrospectively identified for chart review. Propensity score methods created best matched pairs for platinum/pemetrexed versus other platinum-based doublets for head-to-head comparisons of early treatment discontinuation (completed treatment cycles <4), treatment failure (progressive disease or early treatment discontinuation), and adverse events (AE). Conventional multiple logistic regression analyses were also performed to confirm the impact of the studied platinum-based doublets on early treatment discontinuation, treatment failure, and hematological AE using vinorelbine/platinum as reference. Results: 1,846 patients were included to create propensity score matched treatment groups for platinum/pemetrexed versus docetaxel (95 pairs), paclitaxel (118 pairs), gemcitabine (199 pairs), and vinorelbine (72 pairs)-contained doublet, respectively. Platinum/pemetrexed was associated with significantly lower risks of early treatment discontinuation (odds ratio (OR) ranged from 0.239, p = 0.001 relative to platinum/docetaxel to 0.389, p = 0.003 relative to platinum/paclitaxel) and treatment failure (OR ranged from 0.257, p < 0.001 relative to platinum/paclitaxel to 0.381, p < 0.001 relative to platinum/gemcitabine) than the other four studied doublets. Platinum/pemetrexed was also associated with several significantly lower hematological AE rates, such as versus platinum/paclitaxel (any hematological AE: OR 0.508, p = 0.032), platinum/gemcitabine (i.e., any hematological AE: OR 0.383, p < 0.001; anemia: OR 0.357, p < 0.001; thrombocytopenia: OR 0.345, p < 0.001) or platinum/vinorelbine (i.e., neutropenia: OR 0.360, p = 0.046; anemia: OR 0.181, p = 0.014) in matched patients. Further conventional logistic regression analyses indicated that pemetrexed/platinum was ranked lowest for the risks of early treatment discontinuation (OR 0.326, p < 0.001), treatment failure (OR 0.460, p < 0.001), and any hematological AE (OR 0.329, p < 0.001). Conclusions: Pemetrexed plus platinum had significantly superior clinical effectiveness as compared to the other platinum-based doublets with third-generation cytotoxic agents and was also associated with several lower hematological toxicity rates than gemcitabine or vinorelbine-based doublet in the first-line setting for advNS-NSCLC in Chinese patients.