AbstractEffects of photodynamic therapy (PDT) using the anthraquinone hypericin were explored with OVCAR‐5 cells in vitro. Irradiation resulted in ER > lysosomal photodamage. Paraptosis was identified as a primary death pathway resulting from ER perturbation. This is characterized by an extensive pattern of cytoplasmic vacuole formation. As the PDT dose increased, apoptotic death was also detected. The cytoprotective effect of autophagy, observed when certain other subcellular sites are PDT targets, appears to be absent. These results, together with prior evidence that paraptosis can be lethal to cells with an impaired apoptotic pathway, suggest a role for agents with this targeting profile in photodynamic therapy. A limitation to be overcome for hypericin is a suboptimal absorbance profile.