Both types of diabetes are characterized by beta-cell failure and death, leading to insulin insufficiency. Very limited information is currently available about the ultrastructural alterations of beta cells in human diabetes. Our aim was to provide a comprehensive ultrastructural analysis of human pancreatic islets in type 1 (T1D) and type 2 (T2D) diabetic patients. We performed a morphometric electron microscopy evaluation of beta cells obtained from the pancreas of 8 nondiabetic (ND), 5 T1D, and 8 T2D organ donors. A lower amount of beta cells was found in both T1D and T2D than in ND islets, whereas alpha cells were increased only in T2D. An increased number of bi-hormonal cells (showing both insulin and glucagon granules in their cytoplasm) were found in T1D. Insulin granules were less represented in T2D than in ND beta cells, whereas no significant changes were found in T1D. Volume density of the endoplasmic reticulum was increased in T2D and unchanged in T1D; mitochondria number and volume were significantly higher in T2D than in ND beta cells, whereas no significant differences were found in T1D. In both T1D and T2D, more beta cells showed signs of apoptosis than in ND. Our results show that in each type of diabetes, beta cells exhibit specific ultrastructural alterations, whose better understanding might improve therapeutic strategies.