To compare the efficacy of casein phosphopeptide (CPP)-amorphous calcium phosphate (ACP) MI Varnish (GC America, Inc, Alsip, IL) and ProSeal (Reliance Orthodontic Products, Itasca, IL) sealant in preventing the development of white spot lesions (WSLs) in orthodontic patients. This prospective randomized clinical trial included 40 orthodontic patients 12-17 years of age. One group had sealants placed on their anterior maxillary teeth, with reapplications every 3 months. The other group had MI Varnish applied every 4-6 weeks. WSL formation and oral hygiene were evaluated at the initial appointment before bonding (T1) and 12 months later (T2). Standardized digital photographs were analyzed using the enamel decalcification index (EDI). Statistical comparisons were made using independent and paired-sample t-tests as well as chi-square tests. In this trial, 43% of patients and 15% of teeth developed new WSLs. Lateral incisors showed the highest incidence of decalcification and WSL formation. WSL formation and EDI score increases during treatment were significantly greater in the gingival region than in the mesial, distal, or incisal regions. Of the EDI scores at T2, 93.8% were 0 and 5.5% were 1. Poor oral hygiene at T2 showed a high positive predictive value (76%) for the development of WSLs. There were no statistically significant between-group differences for the development of WSLs. MI Varnish and ProSeal sealant provided similar levels of protection during the first 12 months of fixed orthodontic treatment. The severity of the WSLs that developed was minimal. WSLs were most likely to develop on lateral incisors and in the gingival regions of teeth, especially among patients with poorer oral hygiene.