This study aimed to compare patients' perception of postoperative pain following single- and multiple-visit endodontic therapy, and to evaluate associations between anxiety and genetic polymorphisms in the DRD2, ANKK1 and COMT genes. In this clinical trial, 67 patients were included in the first phase (34 single visit, 33 multiple visits), and 25 participated in the second phase. Saliva was collected for genetic analysis, and the State-Trait Anxiety Inventory was applied preoperatively. Postoperative pain (presence and intensity) was recorded at 24, 48 and 72 h. The number of visits was not associated with postoperative pain (p = 0.806); pain intensity was highest at 24 h in both groups (p < 0.001). Moderate anxiety was significantly associated (p < 0.05) with pain in single- and multiple-visit. A genetic association was observed between the COMT rs174675 polymorphism and the outcome (p = 0.018), with greater pain reported by individuals with the CT genotype. (#RBR-47ngbg3).