This trial assessed post-operative pain and healing of apical periodontitis following endodontic therapy with a reciprocating system compared to a crown-down technique with hand files and lateral compaction filling. One-hundred and twenty nonvital anterior teeth with apical periodontitis were randomly treated using either a reciprocating single file followed by matching-taper single-cone filling or a hand file and lateral compaction filling. Postoperative pain was assessed during the 7 days after the treatment, using a visual analogue scale and a verbal rating scale. Apical healing was assessed using the periapical index score after a 12-month follow-up. The hypothesis tested was that both protocols were equivalent and present similar effectiveness in healing periapical lesions. Data were analyzed through two one-sided tests, t-tests, as well as Mann-Whitney and Chi-squared tests (α = 0.05). Logistic regression was used to investigate the association of clinical and demographic factors with the success of treatment. Regardless of the assessment time, no difference in incidence (38%-43% at first 24h), intensity of postoperative pain, and incidence of flare-up (≈ 3%) was observed between the two endodontic protocols. Both protocols resulted in a similar healing rate of apical periodontitis. After 12 months, the success rate ranged from 73% to 78% and the difference between the treatments fell within the pre-established equivalence margin (-0.1; -0.41 to 0.2). Endodontic treatment combining a reciprocating single file with matching-taper single cone showed similar clinical effectiveness to the treatment using hand-file instrumentation and the lateral compaction filling.