This book constitutes the refereed proceedings of the 6th International Workshop on Simulation and Synthesis in Medical Imaging, SASHIMI 2021, held in conjunction with MICCAI 2021, in Strasbourg, France, in September 2021.*The 14 full papers presented were carefully reviewed and selected from 18 submissions. The contributions span the following broad categories in alignment with the initial call-for-papers: methods based on generative models or adversarial learning for MRI/CT/ microscopy image synthesis, and several applications of image synthesis and simulation for data augmentation, image enhancement, or segmentation.*The workshop was held virtually.