BACKGROUND AND OBJECTIVES:The literature suggests that the enzyme nitric oxide synthase (NOS) plays an important role in both periodontal disease (PD) and orofacial pain (OP), although few studies associate these two conditions simultaneously. The objective of this study was to evaluate the expression of the NOS enzyme in PD and OP, in comparison to those patients who did not present PD and/or OP. CONTENTS: Seven electronic databases (Pubmed, Web of science, Scopus, Cochrane Library, BBO, LILACS, Clinical trial) were used to identify the potentially relevant studies published until April 2021. The research resulted in 1,960 studies, of which 11 were selected to be critically evaluated. Two independent reviewers selected titles and abstracts using the criteria defined in the PECO question (Population, Exposure, Comparison, Outcome). The methodological evaluation of the selected studies was carried out according to the Effective Public Health Practice Project (EPHPP). CONCLUSION: Scientific evidence demonstrated that NOS may play a key role in the pathogenesis of PD and OP, since its expression is increased in patients with these conditions. However, genetic studies on endothelial nitric oxide synthase (eNOS) gene mutations in patients with migraine and cluster headache did not indicate the expected susceptibility to pain. In addition, studies on the association of NOS expression in PD and OP, occurring simultaneously, are scarce. This review may supportThe expression of the nitric oxide synthase enzyme in periodontal disease and orofacial pain: systematic review A expressão da enzima óxido nítrico sintase na doença periodontal e na dor orofacial: revisão sistemática