To differentiate inoperable non-small cell lung cancer (NSCLC) subtypes by mono-exponential (MEM), bi-exponential (BEM), and stretched- exponential models (SEM) intravoxel incoherent motion (IVIM), and 18F-FDG PET parameters.A total of 106 cases of NSCLC were included in this analysis, of which 68 cases were adenocarcinoma (AC) and 38 cases were squamous cell carcinoma (SCC). MEM derived parameter ADC; BEM derived parameters D, D*, and f, SEM derived parameters α, DDC; and 18F-FDG PET derived parameters MTV, SUVmax, and TLG were recorded and compared. Area under the receiver operating characteristic curve (AUC) was performed for diagnostic efficacy.SUVmax, MTV and TLG were lower and ADC, f, D and DDC were higher in AC than in SCC (p all < 0.001), whereas D* and α were not significantly different (p = 0.824, 0.152). Logistic regression analysis showed that the stage, ADC, and TLG were independent predictors for identification of SCC and AC, and when combined they showed best diagnostic result (AUC, 0.906; sensitivity, 79.41%; specificity, 94.74%), which was higher than any single clinical factor (maximum diameter, sex smoking, stage, and CT readout; AUC = 0.725, 0.686, 0.707, 0.721, and 0.666, respectively), IVIM (ADC, f, and D; AUC = 0.772, 0.686, and 0.696, respectively) or 18F-FDG PET-derived variable (SUVmax, MTV, and TLG; AUC = 0.693, 0.712, and 0.774, respectively).The stage, ADC, and TLG were independent predictors for differentiating subtypes of inoperable NSCLC, and when combined they showed optimal diagnostic performance and could be a superior imaging marker.© 2025. The Author(s).