Vascular-targeted photodynamic therapy (PDT) is an important strategy for cancer therapy. Conventional vascular-targeted PDT has been achieved by passive photosensitizer (PS) delivery, which involves a high risk of adverse effects. Active PS delivery is urgently required for vascular-targeted PDT. Although endothelial cells and pericytes are major cellular components of tumor blood vessels, little attention has been paid to pericyte-targeted PDT for cancer therapy. PDGFRβ is abundantly expressed in the pericytes of various tumors. In this experiment, a dimeric Z affibody with a 0.9 nM affinity for PDGFRβ was produced. The Z affibody showed PDGFRβ-dependent pericyte binding. Intravenously injected Z affibody was predominantly distributed on pericytes and thus accumulated in LS174T tumor grafts. The conjugate of the Z affibody and IR700 dye, i.e. Z, bound to PDGFRβ pericytes but not to PDGFRβ LS174T tumor cells. Accordingly, Z-mediated PDT in vitro induced the death of pericytes but not of LS174T tumor cells. In mice bearing LS174T tumor grafts, Z-mediated PDT damaged tumor blood vessels, thus inducing tumor destruction by intensifying tissue hypoxia. The average mass of tumor grafts administered with Z-mediated PDT was approximately 20-30% of that of the control, indicating that pericyte-targeted PDT is efficient for cancer therapy. In addition, Z-mediated PDT increased the tumor uptake of TNF-related apoptosis-inducing ligand (TRAIL) injected post-illumination. Consequently, combination therapy of Z-mediated PDT and TRAIL showed greater tumor suppression than Z-mediated PDT- or TRAIL-based monotherapy. These results demonstrated that active vascular-targeted PDT could be achieved by using Z affibody-directed delivery of PS.