BACKGROUND/AIM: In patients with thyroid transcription factor-1 (TTF-1)-negative non-squamous non-small cell lung cancer (NS-NSCLC), the efficacy of pemetrexed and immunotherapy has been reported to be limited, and the optimal treatment strategy remains unclear. Recent studies have suggested that bevacizumab may improve outcomes; however, robust evidence is still lacking. This study aimed to clarify the clinical characteristics of responders to first-line treatment in patients with TTF-1-negative NS-NSCLC and identify predictive factors for treatment response, proposing an optimal treatment strategy. PATIENTS AND METHODS: A retrospective analysis was conducted on patients with TTF-1-negative NS-NSCLC. Patients were classified into responder and non-responder groups based on first-line treatment efficacy, and predictive factors associated with treatment response were analyzed. RESULTS: Among the 29 patients included, seven (24.1%) were classified as responders. Platinum-based combination therapy was significantly more common in the responder group (0.023). The neutrophil-to-lymphocyte ratio was significantly lower in the responder group (0.001). Multivariate analysis demonstrated that the addition of bevacizumab was an independent predictor of treatment response (odds ratio=33.406; 95% confidence interval=1.288-860.210; 0.035). Overall survival was significantly longer in the responder group compared to the non-responder group (0.008). CONCLUSION: In the treatment of TTF-1-negative NS-NSCLC, platinum-based combination therapy, particularly with the addition of bevacizumab, improved response rates and led to prolonged survival.