Disclosed are structures and methods of forming the structures so as to have a photodetector isolated from a substrate by stacked trench isolation regions. In one structure, a first trench isolation region is in and at the top surface of a substrate and a second trench isolation region is in the substrate below the first. A photodetector is on the substrate aligned above the first and second trench isolation regions. In another structure, a semiconductor layer is on an insulator layer and laterally surrounded by a first trench isolation region. A second trench isolation region is in and at the top surface of a substrate below the insulator layer and first trench isolation region. A photodetector is on the semiconductor layer and extends laterally onto the first trench isolation region. The stacked trench isolation regions provide sufficient isolation below the photodetector to allow for direct coupling with an off-chip optical fiber.