The aim of this study is to quantitatively evaluate the effect of irrigation activation performed with standard needle irrigation (SNI) and laser activated irrigation (LAI) tips of different geometric designs on organic tissue loss in the periapical area of teeth with immature apex. Fifteen single-rooted and canal teeth and seventy-five bovine mucosae were used in this study. An experimental model was constructed, and bovine mucosae were placed in the periapical area. Samples were randomly divided into five groups according to the irrigation activation method (n = 15): SNI, PIPS-flat (F), PIPS-radial (R), SWEEPS-flat (F) and SWEEPS-radial (R). Root canals were irrigated with totally 15 mL of 2% NaOCl for three irrigation cycles. Bovine mucosae were weighed before and after the irrigation activation protocols. The difference between the initial and final weights measured organic tissue loss. One-way analysis of variance was performed, followed by post-hoc Tukey significant difference test (p <
0.05). The amount of organic tissue loss in PIPS-R was found to be significantly higher compared to PIPS-F (p <
0.05). However, there was no significant difference in the amount of periapical organic tissue loss among all other tested irrigation activation methods (p >
0.05). All irrigation activation methods caused organic tissue loss. PIPS-R caused more organic tissue loss than PIPS-F, while no difference was found between SWEEPS-F and SWEEPS-R used at the same power setting.