BACKGROUND This report includes outcomes for a group of patients with significant periapical lesions who were treated and evaluated in two single-arm, multicenter, prospective, nonsignificant risk clinical studies. METHODS Forty-five teeth were from 45 patients who met the inclusion criteria and consented for the clinical studies and were diagnosed with periapical lesions with periapical index score ≥3. Patients were treated with a standardized treatment protocol including instrumentation to an apical diameter of #20 without orifice enlargement, the GentleWave Procedure, and warm vertical obturation. Clinical signs and radiographic assessments were evaluated at 12 months to assess healing. Success was classified as healing or healed and accounted for the cumulative success rate of healing. Statistical analyses were performed by using Fisher exact test, Pearson correlation, and multivariate logistic regression analyses. RESULTS At 12 months, 44 of 45 teeth (97.8%) were evaluated. The cumulative success rate for the GentleWave Procedure was 97.7%. Forty-three of 44 teeth were completely functional; all teeth had complete resolution for measured indices of mobility, soft tissue lesions, sinus tract, and furcation involvement. No patients experienced moderate or severe pain at 2, 7, and 14 days after procedure. Although only 1 patient was unsuccessful and the presence of clinical symptoms and type of periradicular diagnosis at 12 months were correlated with an unsuccessful outcome, the analyses were limited by the sample size. CONCLUSIONS In this case series analysis, treatment of sizable periapical lesions with the GentleWave Procedure resulted in a success rate of 97.7% at 12-month re-evaluation.