The aim of this study was to evaluate the ability of a PIPS (photon-induced photoacoustic streaming) Er:YAG laser to reduce the root canal system bacterial count in vivo in comparison to the traditional irrigation technique. The post-operative patients' quality of life (QoL) after endodontic therapy was evaluated through a questionnaire. Fifty-four patients affected by pulp necrosis with or without apical periodontitis biofilm disease were selected for endodontic treatment and randomly assigned to Group A ( = 27) with traditional irrigation and Group B ( = 27), with PIPS irrigation applied according to the protocol. Shaping was performed with ProGlider and ProTaper Next, and irrigation was performed with 5% NaOCl and 10% EDTA. Intracanal samples for culture tests were collected before and after irrigation. The microbiological analysis was evaluated by the Kolmogorov-Smirnov normality and Mann-Whitney tests ( < 0.05). A self-assessment questionnaire was used to evaluate the QoL during the 7 days after treatment; differences were analysed with Student's -test. Irrigation with the PIPS device was significantly effective in reducing bacterial counts, which were higher for facultative than obligate anaerobic strains, particularly for Gram-negative bacteria, without statistical significance ( > 0.05). There were no significant differences among the QoL indicators, except for the maximum pain ( = 0.02), eating difficulty ( = 0.03) and difficulty performing daily functions ( = 0.02) in the first few days post-treatment. PIPS may represent an aid to root canal disinfection not affecting the patients' QoL, particularly for the first day after treatment.