The majority of ultrafast temperature sensitive liposome (uTSL) formulations reported in the literature deliver the highly membrane permeable drug, doxorubicin (DOX). Here we report on the study of the uTSL formulation, HaT (Heat activated cytoToxic, composed of the phospholipid DPPC and the surfactant Brij78) loaded with the water-soluble, but poorly membrane permeable anticancer drugs, gemcitabine (GEM) and oxaliplatin (OXA). The HaT formulation displayed ultrafast release of these drugs in response to temperature, whereas attempts with LTSL (Lyso-lipid Temperature Sensitive Liposome, composed of DPPC, MSPC, and DSPE-PEG) were unsuccessful. HaT-GEM and HaT-OXA both released >80% of the encapsulated drug within 2 min at 40-42 °C, with <5% drug leakage at 37 °C after 30 min in serum. The pharmacokinetic profile of both drugs was improved by formulating with HaT relative to the free drug, with clearance reduced by 50-fold for GEM and 3-fold for OXA. HaT-GEM and HaT-OXA both displayed improved drug uptake in the heated tumor relative to the unheated tumor (by 9-fold and 3-fold, respectively). In particular, HaT-GEM showed 25-fold improved delivery to the heated tumor relative to free GEM and significantly enhanced antitumor efficacy with complete tumor regression after a single dose of HaT-GEM. These data suggest that uTSL technology can also be used to deliver nonmembrane permeable drugs via an intravascular ultrafast release mechanism to great effect.