Introduction Our objective was to evaluate the efficacy of a fluoridated varnish in preventing white spot lesions in patients with fixed appliances. A laser-induced fluorescence device was used to determine any correlations between the degree of demineralization and the length of the observation period, the arch sector, the frequency of varnish application, and the specific tooth site. Methods A split-mouth study design was used for 24 orthodontic patients, allocated randomly to 2 subgroups with differing frequencies of Duraphat varnish (Colgate-Palmolive, New York, NY) application. Repeated measures of the degree of demineralization were taken on the vestibular surfaces of 12 teeth (6 varnished and 6 unvarnished controls). Measurements were taken at 4 sites using a DIAGNOdent Pen 2190 laser (KaVo, Biberach an der Riss, Germany) and then subjected to statistical analysis. Results Generalized linear model and coefficient model analysis showed differences in the degrees of demineralization between treated and untreated teeth, but this was not statistically significant in terms of time point, frequency of application, or specific tooth site. However, when we analyzed the position of the teeth, the varnished anterior teeth showed a statistically significant reduction in demineralization compared with their unvarnished counterparts. Conclusions Periodic application of fluoride varnish can offer some protection against white spots, but not to a statistically significant degree if the patients have excellent oral hygiene.