Introduction White spots (WS) related to orthodontic treatment are severe cariologic and cosmetic complications, but they are shown to be partially reduced by remineralization or abrasion in short-term follow-ups. In this prospective study, we quantitatively analyzed changes in WS in general and in treatment-related white spot lesions (WSL) during orthodontic treatment and at a 12-year follow-up after treatment. In addition, we quantitatively compared the effects of an acrylic bonding material vs a glass ionomer cement (GIC) on WSL. Methods Sum areas of WS and WSL were calculated on scans of standardized photos of the vestibular surfaces of 4 teeth in consecutive orthodontic patients (median treatment time, 1.7 years) bonded with the 2 materials in a split-mouth design. Comparisons were made in 59 patients before treatment (BF), at debonding (T0), at 1 year (T1), and at 2 years (T2), and in 30 patients at a 12-year follow-up (T3) with the Friedman test followed by pairwise comparisons with the Wilcoxon matched-pairs signed rank test. Differences of the effects of acrylic vs GIC on the sum areas of WSL were tested for each observation period with the Mann-Whitney U test. Results Increases in the sum areas of WS and WSL from BF to T0 ( P <0.001) were followed by significant decreases at T1 ( P <0.001) and T2 ( P <0.01 for WS; P <0.001 for WSL). Significant changes were also found in the sum areas for WS at T3 compared with T2 ( P <0.01), but not for WSL ( P = 0.328). The sum areas of WS and WSL at T3 did not return to BF levels ( P <0.001). Sum areas of WSL were higher for surfaces bonded with acrylic compared with GIC for each observation period from BF to T2 ( P >0.001), and from T2 to T3 ( P >0.05). Conclusions Although significantly reduced during the 12-year follow-up and significantly lower with the GIC than the acrylic material at bonding, WSL are a cariologic and cosmetic problem for many orthodontic patients.