The four-volume set LNCS 11070, 11071, 11072, and 11073 constitutes the refereed proceedings of the 21st International Conference on Medical Image Computing and Computer-Assisted Intervention, MICCAI 2018, held in Granada, Spain, in September 2018. The 373 revised full papers presented were carefully reviewed and selected from 1068 submissions in a double-blind review process. The papers have been organized in the following topical sections: Part I: Image Quality and Artefacts; Image Reconstruction Methods; Machine Learning in Medical Imaging; Statistical Analysis for Medical Imaging; Image Registration Methods. Part II: Optical and Histology Applications: Optical Imaging Applications; Histology Applications; Microscopy Applications; Optical Coherence Tomography and Other Optical Imaging Applications. Cardiac, Chest and Abdominal Applications: Cardiac Imaging Applications: Colorectal, Kidney and Liver Imaging Applications; Lung Imaging Applications; Breast Imaging Applications; Other Abdominal Applications. Part III: Diffusion Tensor Imaging and Functional MRI: Diffusion Tensor Imaging; Diffusion Weighted Imaging; Functional MRI; Human Connectome. Neuroimaging and Brain Segmentation Methods: Neuroimaging; Brain Segmentation Methods. Part IV: Computer Assisted Intervention: Image Guided Interventions and Surgery; Surgical Planning, Simulation and Work Flow Analysis; Visualization and Augmented Reality. Image Segmentation Methods: General Image Segmentation Methods, Measures and Applications; Multi-Organ Segmentation; Abdominal Segmentation Methods; Cardiac Segmentation Methods; Chest, Lung and Spine Segmentation; Other Segmentation Applications. .