Objectives This study assessed the influence of preparation size on the efficacy of shock wave–enhanced emission photoacoustic streaming (SWEEPS) and conventional irrigation (CI) on removal of accumulated hard tissue debris (AHTD) from isthmus-containing mandibular molars using micro-computed tomographic analysis. Materials and methods Sixty extracted mandibular molars with two mesial canals connected by an isthmus were selected. Canals were shaped with Mtwo instruments (VDW, Munich, Germany) up to sizes 25/.06, 40/.04 or 40/.06 (n = 20), and specimens were distributed into 2 final irrigation groups (n = 10): SWEEPS and CI. Roots were scanned at a resolution of 10.5 µm before and after preparation and final irrigation. Data sets were co-registered, and the percentage reduction of AHTD calculated for each specimen was statistically compared using analysis of variance with a of 5% significance level. Results The preparation size did not significantly influence the percentage reduction of AHTD (p < 0.05), whereas the final irrigation technique had a significant effect on debris removal (p < 0.05). A significant reduction of AHTD was achieved after final irrigation in all groups (p < 0.05); however, SWEEPS was associated with a significantly greater percentage reduction of debris than CI (p < 0.05). None of the specimens presented a completely clean isthmus. Conclusions Removal of AHTD was not significantly affected by the preparation size. SWEEPS was associated with significantly less debris than CI. Clinical relevance SWEEPS performed significantly better than CI regarding the removal of AHTD from isthmus-containing mandibular molars irrespective of the preparation size.