The effect of local administration of osteocalcin (OC) on experimental tooth movement was examined in the rat. The maxillary first molar was first moved mesially with an initial tipping force of 30 g with a closed-coil spring anchored to the incisor for 10 days (n = 48). Three experimental groups (n = 8) were injected with purified rat OC at doses of 0.1, 1, and 10 micrograms, respectively. The injection into the palatal bifurcation site of the first molar was repeated daily. The control groups (n = 8) were injected with rat serum albumin (10 micrograms), phosphate buffered saline (PBS), or were not injected. Tooth movement was evaluated daily by measuring the inter-cuspal distance between the first and the second molars on a precise plaster model. The cumulative tooth movement (mm) in the 1-microgram OC-injected groups was significantly more than that in all of the control groups on day 9. The rate of tooth movement (mm/day) showed periodical elevation, with high values on days 1, 4, 7, and 9. Acceleration of tooth movement by OC was significant in the early experimental period. Subsequently, acceleration of early tooth movement by OC was histologically evaluated (n = 40). Each of four animals from the control (PBS, n = 20) and the experimental (1 microgram OC, n = 20) groups was killed daily up to 5 days. A significantly larger number of osteoclasts accumulated on the mesial alveolar bone surface in the 1-microgram OC-injected group on day 3 than that observed in control group. These results suggest that administration of OC accelerates orthodontic tooth movement due to enhancement of osteoclastogenesis on the pressure side, primarily in the early experimental period.