Purpose: Based on an exceptionally durable response to pemetrexed observed in some patients with metastatic NSCLC, the predictive value of pemetrexed sensitivity to outcomes of subsequent systemic treatment was investigated. Methods: We retrospectively reviewed the patients with metastatic non-squamous NSCLC treated with pemetrexed monotherapy as their first- or second-line chemotherapy between November 2006 and February 2015. Good (top 5% longest) and poor responders (bottom 12% shortest) were defined according to the duration of pemetrexed maintenance. The first and second post-pemetrexed (PP) systemic treatments were defined as PP1 and PP2 therapies, respectively, to define their progression-free survivals (PFS) as PFS1 and PFS2. Results: In a total of 100 patients, 86% of patients received pemetrexed as their second-line chemotherapy, and 34% were classified as good responders. Good and poor responder groups showed 20.5 months and 0.7 months of the median duration of responses, respectively. PP1 and PP2 therapies were done in 74% and 41.9% of patients after failure to pemetrexed. To our surprise, disease control rate (DCR) was significantly higher in the good responder group than poor responder group (69.6% vs 37.3%, p = 0.010) in patients treated with PP1 therapy, and median PFS1 was also significantly longer (5.2 vs 2.2 months, p < 0.01) regardless of the type of subsequent systemic treatment. Meanwhile, pemetrexed sensitivity did not affect DCR or PFS of patients who received PP2 therapies. Conclusions: Patients who achieved durable response to pemetrexed might obtain greater therapeutic benefits from subsequent systemic treatment in metastatic non-squamous NSCLC without targets, which could potentiate more effective post-pemetrexed treatment strategy.