Purpose: To evaluate the 2-year clinical performance of three self-etching adhesives and one etch-and-rinse adhesive (control) in posterior composite restorations. Materials and Methods: Upon approval by the Institutional Review Board, 121 restorations were inserted in 38 subjects. The adhesives were applied as per manufacturers' instructions. Preparations were restored with a nanofilled composite resin (Filtek Supreme, 3M ESPE) and evaluated at baseline, 6 months, 1 year, and 2 years. Statistical analyses included the McNemar and the Mann-Whitney non-parametric tests (p 0.05). Results: At 2 years, 91 out of 121 restorations were evaluated using the USPHS modified criteria. The number of alpha ratings decreased significantly from baseline to 2 years for Adper Prompt L-Pop, Clearfil S3 Bond, and iBond in the categories color match, marginal staining, and marginal adaptation. For One-Step Plus, only marginal staining was significantly worse at 2 years than at baseline. Postoperative sensitivity to air improved significantly for One-Step Plus at 2 years, but this improvement was already detected at 1 year. When the 2-year evaluation criteria were pooled by pairs of adhesives, One-Step Plus resulted in a significantly greater number of alfa ratings for marginal adaptation than the other three adhesives. On the other hand, iBond resulted in a significantly lower number of alfa ratings than any of the other 3 adhesives for color match and marginal staining. Adper Prompt L-Pop, Clearfil S3 Bond, and One-Step Plus resulted in a statistically similar number of alfa ratings for marginal staining and color match. There were no significant differences in any of the evaluation criteria between Clearfil S3 Bond and Adper Prompt L-Pop. Conclusion: Only One-Step Plus, the etch-and-rinse adhesive, resulted in good marginal adaptation at 2 years. One of the self-etching adhesives, iBond, resulted in unacceptable clinical performance. Keywords: clinical trial, dental bonding, self-etching