Background and Objectives We introduce and clinically examine a new concept of skin treatment called fractional photothermolysis (FP), achieved by applying an array of microscopic treatment zones (MTZ) of thermal injury to the skin. Study Design/Materials and Methods Two prototype devices emitting at 1.5 μm wavelength provided a pattern of micro‐exposures with variable MTZ density. Effects of different MTZ densities were tested on the forearms of 15 subjects. Clinical effects and histology were assessed up to 3 months after exposure. Treatment of photoaged skin on the periorbital area in an additional 30 subjects receiving four treatments over a period of 2–3 weeks was also tested. Tissue shrinkage and clinical effects were assessed up to 3 months after treatment. Results Pattern densities with spacing of 250 μm or more were well tolerated. Typical MTZ had a diameter of 100 μm and penetrated 300 μm into the skin. Reepithelialization was complete within 1 day. Clinical effects were assessed over a 3‐month period. Histology at 3 months revealed enhanced undulating rete ridges and increased mucin deposition within the superficial dermis. Periorbital treatments were well tolerated with minimal erythema and edema. Linear shrinkage of 2.1% was measured 3 months after the last treatment. The wrinkle score improved 18% (P<0.001) 3 months after the last treatment. Conclusions FP is a new concept for skin restoration treatment. Safety and efficacy were demonstrated with a prototype device. Further clinical studies are necessary to refine the optimum parameters and to explore further dermatological applications. Lasers Surg. Med. 34:426–438, 2004. © 2004 Wiley‐Liss, Inc.