BACKGROUND In this study, we tested the efficacy of a tooth sealant polish (Biscover LV; Bisco, Schaumberg, Ill) to prevent enamel demineralization (white spot lesions) for the full duration of orthodontic treatment with fixed appliances. The trial design was an alternating-tooth split-mouth design. METHODS Patients starting treatment with bonded appliances in a private practice were enrolled. The 6 maxillary anterior teeth received the test sealant or no sealant. The nonblinded orthodontists visually examined the teeth immediately after debonding and rated the presence and severity of white spot lesions using a 4-point scale. The difference in incidence of white spot lesions on treated and control teeth was tested with multivariate binary logistic regression for repeated measures by using the generalized estimating equations approach. RESULTS Sixty-five subjects were enrolled, and 3 were lost to follow-up, leaving 62 for analysis. There was a slightly lower incidence of white spot lesions on treated teeth (13.5%; 95% confidence interval, 8.6-18.4) compared with the control teeth (17.7%; 95% confidence interval, 12.4-23.7). This difference was statistically significant in the multivariate model (Wald chi-square, 5.07; df = 1; P = 0.024). The odds ratio was equal to 0.68 (95% confidence interval, 0.47-0.95) that treated teeth would show white spot lesions relative to the control teeth. White spot lesion severity was nearly the same for treated and control teeth (mean ± SD = 1.17 ± 0.47 and 1.20 ± 0.48, respectively; Wald chi-square, 3.03; df = 1; P = 0.082). No serious adverse effects were reported. CONCLUSIONS The sealant did not prevent all white spot lesions for the full duration of treatment. The sealant demonstrated a clinically small but statistically significant ability to prevent white spot lesions.