Recent in vivo and in vitro studies have suggested that medial edge epithelial (MEE) cells covering the lateral palatine shelves do not undergo cell death, but migrate into the oral and nasal epithelium or transform into mesenchymal cells. We, therefore, reexamined the fate of MEE cells during palatal fusion in rat embryos by in situ 3′ nick end labeling of dUTP (TUNEL), electron microscopy, and immunohisto/cytochemistry. TUNEL staining revealed positive nuclei in the medial edge epithelium immediately prior to contact, in epithelial triangles formed between the epithelial seam and nasal or oral epithelium, in epithelial pearls, and in mesenchymal tissue near the epithelium. However, these TUNEL-positive cells were rarely present in the epithelial seam. Electron microscopy revealed MEE cells showing nuclear chromatin condensation and cell shrinkage, and apoptotic bodies in the fusing epithelium; these often contained apoptotic body-like structures as heterophagosomes. By double staining using a laser scanning microscope, TUNEL-positive nuclei were co-localized with lysosomal cysteine proteinases, cathepsin B or L in MEE and mesenchymal cells adjacent to the epithelium. These results suggest that MEE cells undergo apoptosis during the palatal formation, even though they migrate into epithelial triangles or transform into mesenchymal cells. Moreover, apoptotic bodies and cellular debris were phagocytosed by adjacent MEE cells or mesenchymal cells and digested by lysosomal enzymes.