To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant intravenous (IV) liposomal doxorubicin (Doxil) on microvessel morphology and patency and intratumoral drug delivery and retention. There were 133 tumors/animals used in this experiment. First, single subcutaneous tumors (R3230 in Fischer rats and 786-0 in nude mice) were randomly assigned to receive RF ablation alone or no treatment and sacrificed 0-72 hours after treatment. Next, combined RF ablation and liposomal doxorubicin (1 mg given 15 min after RF ablation) was studied in R3230 tumors at 0-72 hours after treatment. Histopathologic assessment, including immunohistochemical staining for cleaved caspase-3, heat-shock protein 70, and CD34, was performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, tumors were randomly assigned to receive RF ablation alone, RF ablation and liposomal doxorubicin, or no treatment (control tumors), followed by IV fluorescent-labeled liposomes (a surrogate marker) given 0-24 hours after RF ablation to permit qualitative assessment. RF ablation alone resulted in enlarged and dysmorphic vessels from 0-4 hours, peaking at 12-24 hours after RF ablation, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area, 47,539 μm(2)±9,544 vs 1,854 μm(2)±458 for RF ablation alone at 15 min; P<.05). Combined RF ablation and liposomal doxorubicin produced similar fluorescence 1 hour after treatment (40.88 AU/μm(2)±33.53 vs 22.1 AU/μm(2)±13.19; P = .14) but significantly less fluorescence at 4 hours (24.3 AU/μm(2)±3.65 vs 2.8 AU/μm(2)±3.14; P<.002) compared with RF ablation alone denoting earlier reduction in microvascular patency. RF ablation induces morphologic changes to vessels within the ablation zone lasting 12-24 hours after treatment. The addition of liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes would likely need to be considered when determining optimal drug administration and imaging paradigms.