Clinical laser settings have traditionally been calibrated on abdominal skin to predict and anticipate patterns of injuries in facial skin. This experimental approach has limitations as facial skin and abdominal skin have differences that may influence the depth of laser injury. The primary objective of this study is to analyze the acute pattern of laser injury in abdominal skin and facial skin samples from the same subject and detail the anatomical and biophysical properties that can influence the laser tissue interaction. The secondary objective is to develop a conversion factor that will allow the prediction laser column depths in facial skin based upon laser column depths in abdominal skin. Fifteen healthy subjects were consented and screened. Two 2 mm spots on the face and abdomen were identified and measured and treated with a fractional CO(2) laser (Lumenis Ltd, Yokneum, Israel), with an energy setting of 15 mj, 300 Hz at a density of 10. Treatment areas were biopsied and analyzed histologically using hematoxylin and eosin and TUNEL staining. Facial skin and abdominal skin have several significant anatomical and biophysical differences (concentration of pilosebaceous units, sebum concentration, and moisture content). Facial tissue demonstrated divergence of laser energy around pilosebaceous units and lateral spread of laser energy along blood vessels. These differences cause attenuation (28%) of the laser energy and result in column depths that are significantly (P < 0.003) shorter in facial tissues (mean depth 415 µm) in comparison to abdominal tissues (mean depth 582 µm). The variations in anatomic, biophysical, and biomechanical properties in facial skin cause an attenuation of the laser column depths in facial skin when compared to abdominal skin. A correction factor of 28% is required to predict the depth of laser columns in facial skin based on laser column depths observed in abdominal skin. Copyright © 2011 Wiley-Liss, Inc.