This in vitro study evaluated the ability of a warm gutta-percha obturation system Thermafil to fill lateral channels in presence/absence of smear layer. Forty single-rooted extracted human teeth were randomly divided into two groups for which different irrigation regimens were used: group A, 5 ml of 5% NaOCl + 2.5 ml of 3.6% H(2)O(2); group B, 5 ml of 5% NaOCl 5% + 2.5 ml of 17% ethylenediamine tetraacetic acid. A conventional crown-down preparation technique was employed. Obturation was performed using epoxy resin-based cement (AH Plus) and a warm gutta-percha plastic carrier system (Thermafil). Specimens were cleared in methyl salicylate and analyzed under a stereomicroscope to evaluate the number, length, and diameter of lateral channels. Lateral channels were identified in both groups at medium and apical thirds. Additional samples were prepared for scanning electron microscopy inspection to confirm the presence of smear layer in group A, and the absence of smear layer in group B. All lateral channels resulted filled in both groups. No statistically significant differences regarding number, length, and diameter were observed between the two groups. Smear layer did not prevent the sealing of lateral channels.