Orthodontic treatment is based on the biologic principle that prolonged pressure on teeth results in remodeling of periodontal structures, allowing for tooth movement. Periodontal remodeling is a complex process regulated in part by prostaglandins and adversely affected by the use of nonsteroidal anti-inflammatory drugs. We investigated the effects of indomethacin on collagenase activity and procollagen synthesis in rat endothelial cell cultures. Cyclooxygenase inhibition resulted in exacerbation of IL-1 beta-mediated collagenase B (MMP-9) production and activity, as well as attenuation of type IV procollagen synthesis levels by endothelial cells in vitro. Hence, the use of over-the-counter nonsteroidal anti-inflammatory drugs during tooth movement may result in aberrant remodeling of periodontal vasculature and other structures, ultimately affecting orthodontic treatment efficacy. Further studies are needed to establish novel pain relievers that do not interfere with orthodontic processes.