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Purpose To develop a method of biologically guided deep learning for post-radiation 18 FDG-PET image outcome prediction based on pre-radiation images and radiotherapy dose information. Methods Based on the classic reaction–diffusion mechanism, a novel biological model was proposed using a partial differential equation that incorporates spatial radiation dose distribution as a patient-specific treatment information variable. A 7-layer encoder–decoder-based convolutional neural network (CNN) was designed and trained to learn the proposed biological model. As such, the model could generate post-radiation 18 FDG-PET image outcome predictions with breakdown biological components for enhanced explainability. The proposed method was developed using 64 oropharyngeal patients with paired 18 FDG-PET studies before and after 20-Gy delivery (2 Gy/day fraction) by intensity-modulated radiotherapy (IMRT). In a two-branch deep learning execution, the proposed CNN learns specific terms in the biological model from paired 18 FDG-PET images and spatial dose distribution in one branch, and the biological model generates post-20-Gy 18 FDG-PET image prediction in the other branch. As in 2D execution, 718/233/230 axial slices from 38/13/13 patients were used for training/validation/independent test. The prediction image results in test cases were compared with the ground-truth results quantitatively. Results The proposed method successfully generated post-20-Gy 18 FDG-PET image outcome prediction with breakdown illustrations of biological model components. Standardized uptake value (SUV) mean values in 18 FDG high-uptake regions of predicted images (2.45 ± 0.25) were similar to ground-truth results (2.51 ± 0.33). In 2D-based Gamma analysis, the median/mean Gamma Index (<1) passing rate of test images was 96.5%/92.8% using the 5%/5 mm criterion; such result was improved to 99.9%/99.6% when 10%/10 mm was adopted. Conclusion The developed biologically guided deep learning method achieved post-20-Gy 18 FDG-PET image outcome predictions in good agreement with ground-truth results. With the breakdown biological modeling components, the outcome image predictions could be used in adaptive radiotherapy decision-making to optimize personalized plans for the best outcome in the future.