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Abstract Background and Objective The main objective of the present study is to demonstrate the feasibility of utilizing a novel non‐invasive radiofrequency (RF) device to induce lethal thermal damage to subcutaneous adipose tissue only by establishing a controlled electric field that heats up fat preferentially. Study Design/Materials and Methods Adipocyte cells in six‐well plates were subjected to hyperthermic conditions: 45, 50, 55, 60, and 65°C during 1, 2, and 3 minutes. Cell viability was assessed 72 hours after exposure. Two groups of abdominoplasty patients were treated with the RF device during and days before their surgical procedure. Temperatures of cutaneous and subcutaneous tissues were measured during treatment (3 minutes) of the first group. The immediate tissue response to heating was assessed by acute histology. The delayed tissue response was assessed by histology analysis of the second group, 4, 9, 10, 17, and 24 days after treatment (22 minutes). A mathematical model was used to estimate treatment temperatures of the second group. The model uses patient‐based diagnostic measurements as input and was validated with in vivo clinical temperature measurements. Results Cell viability dropped from 89% to 20% when temperature increased from 45 to 50°C during 1 minute exposures. Three minutes at 45°C resulted in 40% viability. In vivo, the temperature of adipose tissue at 7–12 mm depth from the surface increased to 50°C while the temperature of cutaneous tissues was <30°C during RF exposure. Acute and longitudinal histology evaluations show normal epidermal and dermal layers. Subcutaneous tissues were also normal acutely. Subcutaneous vascular alterations, starting at day 4, and fat necrosis, starting at day 9, were consistently observed within 4.5–19 mm depth from the skin surface. Subcutaneous tissue temperatures were estimated to be 43–45°C for 15 minutes. Conclusions A controlled internal electric field perpendicular to the skin–fat interface is selective in heating up fat and, consequently, has the ability to induce lethal thermal damage to subcutaneous adipose tissues while sparing overlying and underlying tissues. In vitro adipocyte cells are heat sensitive to thermal exposures of 50 and 45°C on the order of minutes, 1 and 3 minutes, respectively. In vivo, 15 minutes thermal exposures to 43–45°C result in a delayed adipocyte cellular death response—in this study, 9 days. The novel RF device presented herein effectively delivers therapeutic thermal exposures to subcutaneous adipose tissues while protecting epidermal and dermal layers. Lasers Surg. Med. 42:361–370, 2010. © 2010 Wiley–Liss, Inc.