INTRODUCTION AND OBJECTIVES: The increased diagnosis of small, localized cancers has sparked interest in focal ablation therapies. Numerous technologies exist, and are generally divided into thermalablative techniques such as radiofrequency ablation (RFA) and cryotherapy, or by non-thermal ablative techniques, such as irreversible electroporation (IRE) and photodynamic therapy (PDT). The tissue effect of each modality has been investigated, but a detailed, comparative analysis has not yet been performed. We sought to characterize and contrast the tissue effects of four such techniques in a large animal model. METHODS: Percutaneous image-guided ablation (PDT, IRE, Cryotherapy and RFA) was performed in 16 Yorkshire pigs. Each animal had multiple ablations in the liver, kidney, and pancreas, approximately 1-2 cm in size. Cannula placement was performed using ultrasound or CT imaging. PDT was delivered using WST-11 as the photosensitizer. Contrast-enhanced CT imaging (CECT) was performed post-procedure and at 24 hours following treatment. The treated organs were removed at 4 and 24 hours, and representative slices were sent for H&E, electron microscopy, and staining for collagen and apoptotic activity. RESULTS: Each technology revealed a unique pattern of solid organ tissue injury. At 4 hours after treatment, thermal ablative technologies revealed extensive tissue necrosis and collagen denaturation, while PDT and IRE showed no necrosis with well-demarcated areas of hyperemia and hemorrhage. At 24 hours, all forms of ablation revealed areas of coagulative necrosis. Thermal ablative technologies created irregular lesion boundaries with significant sparing around blood vessels larger than 600 m. PDT ablated blood vessels smaller than 300 m, but spared all blood vessels larger than 400 m in the ablation zone. IRE ablated all blood vessels in the area of effect. PDT revealed the most sharply demarcated zones of necrosis with no heat sink effect. The architecture of extracellular collagen appeared minimally affected by PDT and IRE, but significant denaturation was present in RFA and cryotherapy. CONCLUSIONS: Each method of focal therapy demonstrated unique tissue effects influenced by organ tissue architecture and vascularization. Understanding these differences will be essential in evaluating treatment efficacy and optimizing their therapeutic effects. CECT imaging can provide accurate assessment of both thermal and nonthermal ablative techniques.