Tropical forest fragmentation results in habitat and biodiversity loss and increased carbon emissions. Here, we link an increased likelihood of tropical forest loss to decreasing fragment size, particularly in primary forests. The relationship holds for protected areas, albeit with half the rate of loss compared with all fragments. The fact that disturbance increases as primary forest fragment size decreases reflects higher land use pressures and improved access for resource extraction and/or conversion in smaller fragments. Large remaining forest fragments are found in the Amazon and Congo Basins and Insular Southeast Asia, with the majority of large extent/low loss fragments located in the Amazon. Tropical areas without large fragments, including Central America, West Africa, and mainland Southeast Asia, have higher loss within and outside of protected areas. Results illustrate the need for rigorous land use planning, management, and enforcement in maintaining large tropical forest fragments and restoring regions of advanced fragmentation.