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Purpose: Pemetrexed causes renal impairment. However, few studies have investigated the risk factors associated with pemetrexed-induced renal impairment. This study aimed to investigate the incidence of nephrotoxicity in patients receiving pemetrexed in combination with carboplatin and to identify the associated risk factors. Methods: This single-center retrospective study included patients with lung cancer (including malignant mesothelioma) who underwent pemetrexed-based treatment between May 2019 and August 2022. Nephrotoxicity incidence was evaluated according to the Kidney Disease Improving Global Outcomes diagnostic criteria, and risk factors for nephrotoxicity during pemetrexed treatment were identified using logistic regression analysis. Results: Renal impairment occurred in 17 of 108 patients (15.7 %), with many experiencing irreversible renal function decline after its onset. The risk factors for nephrotoxicity during pemetrexed-based treatment were identified as the total number of cycles (≥ 10) (odds ratio: 7.94, p < 0.01) and its combination with any two non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), or diuretics (odds ratio: 6.30, p < 0.01). Conclusion: Patients receiving pemetrexed treatment are at risk of developing renal impairment, with risk potentially increasing with the number of treatment cycles and concomitant use of NSAIDs, ACEIs/ARBs, or diuretics. However, further studies are required to confirm these findings.