Introduction: Transient inflammatory surface resorption, referred to as orthodontic induced inflammatory root resorption (OIIRR), is an iatrogenic consequence of orthodontic tooth movement. Systemic fluoride has been associated with a reduction of OIIRR. This study aimed to investigate the effects of water fluoridation levels on OIIRR in a clinically applicable human orthodontic model. Methods: Twenty-eight patients who required bilateral maxillary first premolar extraction as part of orthodontic treatment were selected from 2 cities with high and low water fluoridation of >= 2 ppm and <= 0.05 ppm, respectively. Patients were separated into high fluoride (HF) and low fluoride (LF) groups on the basis of water fluoridation levels. Bilateral maxillary first premolar teeth were subjected to 150 g of buccal tipping forces for 12 weeks with reactivation every 4 weeks. Teeth were extracted at the end of 12 weeks. Root resorption crater volume was determined using microcomputed tomography and 3dimensional reconstruction. Results: HF group showed significantly less mean root resorption volume on the palatal root surface when compared with the LF group (P = 0.025). This difference was specifically displayed at palatal apical regions (P = 0.041). When root resorption volumes from the zones of orthodontic pressure (buccal cervical, palatal apical) were combined, the mean difference between HF and LF groups was statistically significant (P = 0.045). Conclusions: Findings of the present study indicated a positive correlation between water fluoridation and the reduction of OIIRR, especially at the zones of orthodontic pressure, using a clinically relevant human orthodontic model.