Aim: To evaluate the effect of hyaluronan (HY) application as monotherapy or as adjunct to non-surgical and/or surgical periodontal therapy. Methods: Literature search was performed according to PRISMA guidelines with the following main eligibility criteria: (a) English or German language; (b) pre- clinical in vivo or human controlled trials; (c) effect size of HY evaluated histolog- ically or clinically. Results: Two pre-clinical in vivo studies on surgical treatment and 12 clinical tri- als on non-surgical and/or surgical treatment were included. Most of the studies were highly heterogeneous, regarding with HY product used and application mode, and of high risk of bias, thus not allowing meta-analysis. The majority of clinical studies described a beneficial, occasionally statistically significant, effect of HY on bleeding on probing (BoP) and pocket depth (PD) reduction (2.28–19.5% and 0.2–0.9 mm, respectively), comparing to controls; no adverse effects were reported. Conclusions: Hyaluronan application as adjunct to non-surgical and surgical perio- dontal treatment seems to have a beneficial, generally moderate, effect on surro- gate outcome variables of periodontal inflammation, i.e., BoP and residual PD, and appears to be safe. The large heterogeneity of included studies, does not allow recommendations on the mode of application or effect size of HY as adjunct to non-surgical and surgical periodontal treatment.