OBJECTIVE To examine the effectiveness of topical phenytoin in preserving the skin viability and increasing acceptance rate of autograft. METHODS We conducted this study in the Central Laboratory Animal House of Jordan University of Science and Technology, Irbid, Jordan during the period from September 2004 to June 2005. Forty-two rats were divided into 2 equal groups; full thickness dorsal skin wound (4 cm2) was created in the rats. Twenty-one rats were treated with phenytoin (10% w/w ointment), the other 21 (control) were treated with standard dressing and Vaseline. An autograft was performed one week after treatment. Rats were examined for the presence of healthy granulation tissue, reduction in wound surface dimensions, and time for complete graft attachment. RESULTS Phenytoin ointment had significantly increased wound bed viability and the rate of graft acceptance (p-value <0.0001). Twenty rats had successful grafting (10% phenytoin); while only 3 rats out of the 21 control had successful grafts. The mean time to complete graft attachment and hair growth in the grafted skin was 6.6 +/- 0.5 days. The mean wound contraction measurements (taken just before grafting) were as follow: control group 59.2 +/- 11.6%, and phenytoin group 55.7 +/- 9.2, difference in skin contractility was not statistically significant. Skin viability was evident by increased vascularity and granular tissue formation at the edges of the wound. CONCLUSION Phenytoin appears to be an effective method for enhancing the take of the full-thickness skin graft. Further clinical use and evaluation of topical phenytoin ointment in skin grafting are merited.