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Objectives : To determine whether two-step ablation using sequential low and high temperature heating can achieve improved outcomes in animal tumor models when combined with chemotherapeutic liposomes (LP). Materials and methods : Balb/c mice bearing 4T1 tumor received paclitaxel-loaded liposomes followed 24 h later by either traditional RFA (70 °C, 5 min) or a low temperature RFA (45 °C, 5 min), or two-step RFA (45 °C 2 min + 70 °C 3 min). Intratumoral drug accumulation and bio-distribution in major organs were evaluated. Periablational drug penetration was evaluated by pathologic staining and the intratumoral interstitial fluid pressure (IFP) was measured directly. For long-term outcomes, mice bearing 4T1 or H22 tumors were randomized into five groups ( n = 8 per group): control (no treatment), RFA alone, LP + RFA (45 °C), LP + RFA (70 °C) and LP + RFA (45 + 70 °C). End-point survivals were compared among the different groups. Results : The greater intratumoral drug accumulation (3.35 ± 0.32 vs. 3.79 ± 0.29 × 10 8 phot/cm 2 /s at 24 h, p = 0.09), deeper periablational drug penetration (45.7 ± 5.0 vs. 1.6 ± 0.5, p < 0.001), and reduced off-target drug deposition in major organs (liver 96.1 ± 31.6 vs. 47.4 ± 1.5 × 10 6 phot/cm 2 /s, p < 0.001) were found when combined with RFA (45 °C) compared to drug alone. For long-term outcomes, 4T1 tumor growth rates for LP + two-step RFA (45 + 70 °C) were significantly slower than those of LP + RFA (70 °C), LP + RFA (45 °C), and RFA alone ( P < 0.01 for all comparisons). End point survival for LP + RFA (45 + 70 °C) was also longer than that for LP + RFA (70 °C) (median 16 vs. 10 days, p = 0.003) or LP + RFA 45 °C (11 days, p = 0.009) and RFA alone (8.3 days, p < 0.001) in 4T1 tumor models. The intratumoral IFP after RFA (45 °C) was significantly lower than baseline RFA (3.3 ± 0.8 vs. 19.2 ± 3.1 mmHg, p < 0.001), but was not measurable after RFA (70 °C). Conclusions : A two-step ablation combined with chemotherapeutic liposomes can achieve better survival benefit compared to traditional RFA in animal models.