Purpose-Machine learning-based approaches now outperform competing methods in most disciplines relevant to diagnostic radiology. Image-guided procedures, however, have not yet benefited substantially from the advent of deep learning, in particular because images for procedural guidance are not archived and thus unavailable for learning, and even if they were available, annotations would be a severe challenge due to the vast amounts of data. In silico simulation of X-ray images from 3D CT is an interesting alternative to using true clinical radiographs since labeling is comparably easy and potentially readily available.Methods-We extend our framework for fast and realistic simulation of fluoroscopy from highresolution CT, called DeepDRR, with tool modeling capabilities. The framework is publicly available, open source, and tightly integrated with the software platforms native to deep learning, i.e., Python, PyTorch, and PyCuda. DeepDRR relies on machine learning for material decomposition and scatter estimation in 3D and 2D, respectively, but uses analytic forward projection and noise injection to ensure acceptable computation times. On two X-ray image analysis tasks, namely (1) anatomical landmark detection and (2) segmentation and localization of robot end-effectors, we demonstrate that convolutional neural networks (ConvNets) trained on DeepDRRs generalize well to real data without re-training or domain adaptation. To this end, we use the exact same training protocol to train ConvNets on naïve and DeepDRRs and compare their performance on data of cadaveric specimens acquired using a clinical C-arm X-ray system.