Background¹⁸F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is valuable for determining presence of viable tumor, but is limited by geographical restrictions, radiation exposure, and high cost.PurposeTo generate diagnostic‐quality PET equivalent imaging for patients with brain neoplasms by deep learning with multi‐contrast MRI.Study TypeRetrospective.SubjectsPatients (59 studies from 51 subjects; age 56 ± 13 years; 29 males) who underwent ¹⁸F‐FDG PET and MRI for determining recurrent brain tumor.Field Strength/Sequence3T; 3D GRE T1, 3D GRE T1c, 3D FSE T2‐FLAIR, and 3D FSE ASL, ¹⁸F‐FDG PET imaging.AssessmentConvolutional neural networks were trained using four MRIs as inputs and acquired FDG PET images as output. The agreement between the acquired and synthesized PET was evaluated by quality metrics and Bland–Altman plots for standardized uptake value ratio. Three physicians scored image quality on a 5‐point scale, with score ≥3 as high‐quality. They assessed the lesions on a 5‐point scale, which was binarized to analyze diagnostic consistency of the synthesized PET compared to the acquired PET.Statistical TestsThe agreement in ratings between the acquired and synthesized PET were tested with Gwet's AC and exact Bowker test of symmetry. Agreement of the readers was assessed by Gwet's AC. P = 0.05 was used as the cutoff for statistical significance.ResultsThe synthesized PET visually resembled the acquired PET and showed significant improvement in quality metrics (+21.7% on PSNR, +22.2% on SSIM, −31.8% on RSME) compared with ASL. A total of 49.7% of the synthesized PET were considered as high‐quality compared to 73.4% of the acquired PET which was statistically significant, but with distinct variability between readers. For the positive/negative lesion assessment, the synthesized PET had an accuracy of 87% but had a tendency to overcall.ConclusionThe proposed deep learning model has the potential of synthesizing diagnostic quality FDG PET images without the use of radiotracers.Evidence Level3Technical EfficacyStage 2