BACKGROUND AND OBJECTIVES This study was designed to examine modes of cell death after photodynamic therapy (PDT). STUDY DESIGN Murine leukemia L1210 cells and human prostate Bax-deficient DU145 cells were examined after PDT-induced photodamage to the endoplasmic reticulum (ER). Phase contrast, fluorescence and electron microscopy were used to identify changes in cellular morphology, chromatin condensation, loss of mitochondrial membrane potential, and formation of phagolysosomes. Western blots were used to assess the processing of LC3-I to LC3-II, a marker for autophagy. Inhibitors of apoptosis and/or autophagy were used to delineate the contributions of the two pathways to the effects of PDT. RESULTS Both apoptosis and autophagy occurred in L1210 after ER photodamage with the latter predominating after 24 hours. In DU145 cells, PDT conditions causing comparable cytotoxicity only initiated autophagy. PI3-kinase inhibitors suppressed autophagy in both cell lines as indicated by inhibition of vacuolization and LC3 processing. CONCLUSIONS Both autophagy and apoptosis were observed in L1210 cells following ER photodamage. In the Bax-deficient DU145 cell line only autophagy was observed. Current information suggests that autophagy can function as either a survival or death pathway. We propose that in the context of PDT, this may also be true.