This study evaluated the amount and depth of root resorption associated with varying concentrations and frequencies of injectable, exogenous prostaglandin E2 (PGE2) in conjunction with orthodontic tooth movement in rats. The sample consisted of 155 maxillary right and left first molars from 88, 8-week old, male Sprague-Dawley rats. The animals were divided into three control groups and two experimental groups. The control animals were divided into one nonappliance and two appliance groups. The experimental animals were divided into 2- and 4-week experimental time periods that were further subdivided based on single and weekly injection intervals of PGE2 and four different injectable concentration levels, i.e., 0.1, 1.0, 5.0, and 10.0 micrograms. A fixed orthodontic appliance was ligated between the maxillary incisors and maxillary first molars with closed-coil nickel-titanium springs. The appliance had an initial activating force of 60 gm. Serial histologic sections of the mesial root of the maxillary first molar were made, and a quantitative histomorphometric analysis of root resorption on the mesial and distal surfaces was performed. This study demonstrated increased root surface resorption when using exogenous PGE2 injections to enhance orthodontic tooth movement over a 2-week period with increasing root resorption on the mesial surface as compared with the distal surface in PGE2 treated teeth. No differences in root resorption were found with either multiple injections or increasing concentration in the 4-week experimental group. Local injection of PGE2 appeared to have no effect on the number or depth of resorption lacunae in either the 2- or 4-week groups.