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Background Immune checkpoint inhibitors have improved outcomes for several malignancies; however, there remains a lack of accurate, non-invasive methods to assess tumor PD-L1 expression levels and guide immunotherapy. This study aimed to evaluate the role of PD-L1-targeted positron emission tomography (PET) imaging in predicting immunotherapy response and prognosis in lung cancer.Methods Four healthy volunteers and 22 treatment-naïve lung cancer patients were prospectively enrolled and underwent [ 68Ga]Ga-PDL1p PET imaging. All patients additionally completed paired baseline [18F]fluorodeoxyglucose ([18F]FDG) PET scans. Of the 22 patients, 17 received ≥3 cycles of immunotherapy combined with chemotherapy and underwent follow-up [18F]FDG PET or CT examinations. The correlations of baseline [68Ga]Ga-PDL1p and [18F]FDG uptake with tumor PD-L1 expression were evaluated. Furthermore, the associations of tumor [68Ga]Ga-PDL1p uptake, [18F]FDG uptake, and PD-L1 expression with immunotherapy response were analyzed, along with their predictive values for immunotherapy efficacy and outcomes.Results Lesions with high PD-L1 expression exhibited significantly higher [ 68Ga]Ga-PDL1p uptake than those with low expression (p=0.007), whereas [18F]FDG uptake showed no significant difference (p=0.499). At baseline, [68Ga]Ga-PDL1p uptake was significantly higher in responders than in non-responders (p=0.008), with an area under the receiver operating characteristic curve of 0.886. In contrast, neither [18F]FDG uptake nor PD-L1 expression levels differed significantly between the two groups. Disease progression occurred in 23.5% of patients (4/17) by the final follow-up. Patients with higher [68Ga]Ga-PDL1p uptake or higher [18F]FDG uptake demonstrated significantly longer progression-free survival (PFS) than those with lower uptake (p=0.033 and p<0.001, respectively). However, no significant difference in PFS was observed between patients with high and low PD-L1 expression, using either a 50% (p=0.487) or 1% (p=0.100) cut-off.Conclusions [ 68Ga]Ga-PDL1p PET outperforms conventional [18F]FDG PET and immunohistochemistry-based PD-L1 assessment in predicting immunotherapy response and prognosis. These findings offer new insights for evaluating immunotherapy efficacy and guiding individualized tumor treatment.