Photobiomodulation therapy (PBMT) has anti-inflammatory, analgesic and regenerative properties. This systematic review aimed to critically appraise the published data of in vivo human randomized clinical trials (RCTs), and present a comprehensive overview of the efficacy of PBMT, as an adjunct to the non-surgical periodontal therapy (NSPT) in the management of periodontitis. The systematic review protocol is registered in the Prospective Register Of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/PROSPERO/; ref CRD 42020169108). With the help of the appropriate key words, structured electronic and manual search strategies were applied to gather the relevant published data on in vivo human RCTs based on this topic. Seventeen papers that met the eligibility criteria were included in this review and subjected to a qualitative assessment. Current evidence lacks adequate information regarding the photobiomodulation (PBM) dosimetry, which is fundamental in establishing a standardized and replicable protocol for future researches. Furthermore, substantial discrepancies in the study methodology and a high risk of bias, arising from the majority of the included papers, abet to the inferior quality of these studies. Ultimately, there is an urgent necessity to conduct further well-designed RCTs in order to determine the effectiveness of PBMT, if any, by taking into consideration the abovementioned confounding factors.This article is protected by copyright. All rights reserved.