Purpose: To evaluate whether it is more effective to complete endodontic treatment in a single visit or in two visits with 1-week intracanal calcium hydroxide medication in symptomatic teeth and teeth with periapical lesions. Materials and methods: One hundred and ninety-nine patients, with one symptomatic tooth or a tooth with a periapical lesion, were randomised, according to a parallel group design, to receive a complete endodontic treatment in a single visit (99 patients) or in two visits with 1-week intracanal calcium hydroxide medication (100 patients), at two centres. Patients were followed for up to 1 year post-treatment and the outcome measures were tooth loss, radiographic healing, any complication, post-treatment pain and amount of painkillers used. Results: Seven patients dropped out from the single-visit and ten patients from the two-visit group (all patients from one centre only). One patient lost his tooth from the single-visit and two patients from the two-visit group (difference in proportion = -0.01; 95% CI: -0.05 to 0.03; P = 0.619). Five single-visit patients and nine two-visit patients experienced one complication each (difference in proportion = -0.05; 95% CI: -0.12 to 0.03; P = 0.278). There were no statistically significant differences in tooth loss and complications. One year after treatment, complete radiographic healing was observed in 22 patients of the single-visit group and in 19 patients of the two-visit group; improvement in 43 patients of the single-visit group and in 54 patients of the two-visit group; and no changes/worsening in 24 patients of the single-visit group and in 15 patients of the two-visit group. There were no statistically significant differences in radiographic healing between the two groups (P = 0.509). Pre-treatment pain was reported by 68 single-visit patients and by 68 two-visit patients; 1-week post-treatment pain was reported by 27 single-visit patients and by 46 two-visit patients, and 2-week post-treatment pain was reported by 2 single-visit patients and 11 two-visit patients. For the first week, an average of 0.53 ± 1.23 tablets was taken by single-visit patients and 1.44 ± 3.32 tablets by two-visit patients. For the second week, no single-visit patients needed tablets and in the two-visit group the average was 0.37 ± 1.72 tablets. Patients of the two-visits group had statistically significant more post-treatment pain at 1 (P = 0.002) and 2 weeks (P = 0.011), and took more ibuprofen tablets at 1 (difference = -0.92; 95% CI: -1.62 to -0.21; P = 0.011) and 2 weeks after treatment (difference = -0.37; 95% CI: -0.72 to -0.03; P = 0.033), than in patients treated in a single visit. Conclusions: One year after treatment, both groups achieved similar clinical results; however, patients endodontically treated in a single visit suffered less postoperative pain and took less analgesics than patients treated in two visits, therefore a single-visit treatment should be recommended.