Purpose: The purpose of this in vitro study was to determine the marginal adaptation of different adhesives, including recently developed self-etching primers, in combination with compomers in Class V cavities. Materials and Methods: In 80 extracted human teeth, divided into 10 groups of 8, Class V cavities were prepared (ca. 4 mm high, 3 mm wide, and 1.5 mm deep) with one half of the margin length in dentin. The one-bottle adhesives Prime & Bond 2.1, Syntac SC, and Espe OSB, and the self-etching primers Rasant F 2000 and Prompt L Pop were used in combination with compomers. Before and after thermocycling (TC), replicas were taken and a quantitative margin analysis using the SEM was performed at a magnification of 200x using defined criteria. Results: The statistical analysis using Kruskal-Wallis and Bonferroni tests showed a significantly (p < 0.05) better marginal adaptation in enamel and dentin for the self-etching primers, and when the one-bottle adhesives were used in combination with the total-etch technique. Conclusion: Self-etching primers improve the marginal adaptation of compomer restorations in enamel.