Objectives: This study aimed to evaluate the effect of copper nanoparticles (CuNp) on the clinical performance of a universal adhesive system used as an etch-and-rinse or self-etch strategy. Methods: A total of 216 class V (non-carious lesions) restorations were randomly placed in 36 subjects according to the following groups: ERcu, adhesive in etch-and-rinse with 0.1% CuNp; ERct, adhesive in etch-and-rinse without CuNp; SEcu, adhesive in self-etch with 0.1% CuNp; and Sect, adhesive in self-etch without CuNp. Restorations were evaluated at baseline and at 6, 12, 18, 36, and 48 months, using the FDI and USPHS criteria. Appropriate statistical analyses were performed (α = 0.05). Results: After 48 months, 14 restorations were lost (two for ERcu, five for SEcu, and seven for SEct) and the retention rates (95% confidence interval [CI]) were 74.1% for ERcu (95% CI 61.1–83.8); 81.5% for ERct (95% CI 69.2–89.6); 64.8% (95% CI 51.5–76.2) for SEcu; and 64.8% (95% CI 51.5–76.2) for SEct, with statistical differences between SEct vs. ERct and SEcu vs. ERct (p < 0.05). No significant differences between the groups were observed when the secondary parameters were evaluated (p > 0.05). Nineteen restorations (two for ERcu, two for ERct, six for SEcu, and nine for SEct) showed minor marginal staining, and 44 restorations (7 for ERcu, 8 for ERct, 14 for SEcu, and 15 for SEct) presented minimal marginal adaptation defects. Significance: This is the first long-term clinical trial to show that the addition of CuNp to a universal adhesive system does not affect clinical performance.
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