The aim of this study was to evaluate the solubility of three types of root canal sealers in three organic solvents used in endodontics. The solubility of calcium-hydroxide-based (Sealer 26), silicon-polydimethylsiloxane-based (RoekoSeal), and zinc-oxide–eugenol based (Endofill and Intrafill) sealers was assessed in eucalyptol, xylol, orange oil, and distilled water. Eighty samples of each filling material were prepared according to the manufacturers’ instructions and then divided into four groups for immersion in solvent for 2 or 10 min. The means of sealer dissolution in solvents were obtained by the difference between the original preimmersion weight and the postimmersion weight in a digital analytical scale. Data were statistically analyzed with the Student’s t test, and multiple comparisons were performed with Student–Newman–Keuls. Xylol and orange oil showed similar effects, with significant solubilization (P<0.05) of the tested cements. Endofill and Sealer 26 did not show any significant difference in solubilization at the two immersion times, whereas RoekoSeal and Intrafill showed a more pronounced solubility at 10 min. The lowest levels of solubilization occurred in RoekoSeal, Sealer 26, Endofill, and Intrafill. It is concluded that xylol and orange oil presented similar solvent effects with a significant solubility of the tested cements.