ABSTRACT: PURPOSE:A major challenge for accurate quantitative SPECT imaging of some radionuclides is the inadequacy of simple energy window-based scatter estimation methods, widely available on clinic systems. A deep learning approach for SPECT/CT scatter estimation is investigated as an alternative to computationally expensive Monte Carlo (MC) methods for challenging SPECT radionuclides, such as 90Y. METHODS:A deep convolutional neural network (DCNN) was trained to separately estimate each scatter projection from the measured 90Y bremsstrahlung SPECT emission projection and CT attenuation projection that form the network inputs. The 13-layer deep architecture consisted of separate paths for the emission and attenuation projection that are concatenated before the final convolution steps. The training label consisted of MC-generated "true" scatter projections in phantoms (MC is needed only for training) with the mean square difference relative to the model output serving as the loss function. The test data set included a simulated sphere phantom with a lung insert, measurements of a liver phantom, and patients after 90Y radioembolization. OS-EM SPECT reconstruction without scatter correction (NO-SC), with the true scatter (TRUE-SC) (available for simulated data only), with the DCNN estimated scatter (DCNN-SC), and with a previously developed MC scatter model (MC-SC) were compared, including with 90Y PET when available. RESULTS:The contrast recovery (CR) vs. noise and lung insert residual error vs. noise curves for images reconstructed with DCNN-SC and MC-SC estimates were similar. At the same noise level of 10% (across multiple realizations), the average sphere CR was 24%, 52%, 55%, and 67% for NO-SC, MC-SC, DCNN-SC, and TRUE-SC, respectively. For the liver phantom, the average CR for liver inserts were 32%, 73%, and 65% for NO-SC, MC-SC, and DCNN-SC, respectively while the corresponding values for average contrast-to-noise ratio (visibility index) in low-concentration extra-hepatic inserts were 2, 19, and 61, respectively. In patients, there was high concordance between lesion-to-liver uptake ratios for SPECT reconstruction with DCNN-SC (median 4.8, range 0.02-13.8) compared with MC-SC (median 4.0, range 0.13-12.1; CCC?=?0.98) and with 90Y PET (median 4.9, range 0.02-11.2; CCC?=?0.96) while the concordance with NO-SC was poor (median 2.8, range 0.3-7.2; CCC?=?0.59). The trained DCNN took ~?40 s (using a single i5 processor on a desktop computer) to generate the scatter estimates for all 128 views in a patient scan, compared to ~?80 min for the MC scatter model using 12 processors. CONCLUSIONS:For diverse 90Y test data that included patient studies, we demonstrated comparable performance between images reconstructed with deep learning and MC-based scatter estimates using metrics relevant for dosimetry and for safety. This approach that can be generalized to other radionuclides by changing the training data is well suited for real-time clinical use because of the high speed, orders of magnitude faster than MC, while maintaining high accuracy.