© 2019 by The EH Angle Education and Research Foundation, Inc. Objectives: To determine the effect of Clinpro 5000, Clinpro Tooth Crème, and MI-Paste Plus on the formation of white spot lesions in patients undergoing orthodontic treatment. Materials and Methods: Three prospective groups with 40 patients undergoing orthodontic treatment in each group were evaluated (total recruitment 120 subjects). The selected product was brushed on for 2 minutes twice daily for 4 months. Subjects were reviewed for 4 months on a monthly basis. The Enamel Decalcification Index (EDI) was used to determine the number of white spot lesions per surface at each visit. Results: 100 subjects (35 using Clinpro 5000, 32 using Clinpro Tooth Crème, and 33 using MI Paste Plus) completed the study. The data lend strong support for Clinpro 5000 providing superior protection against enamel decalcification when compared to Clinpro Cr ème, and mixed support when compared to MI Paste Plus. Conclusions: The use of Clinpro 5000, Clinpro Cr ème, and MI paste Plus all have a reduction effect on white spot lesions when compared to studies reported previously. Clinpro 5000 has a marginally better effect than the two other test pastes. The results of this study can be used by clinicians when deciding the effectiveness of using fluoride dentifrice products to prevent white spot lesions in their orthodontic practice (ClinicalTrials.gov ID: NCT03440996). (Angle Orthod. 2019;89:365-371.