Objectives: Complete bidirectional cavo-tricuspid isthmus (CTI) block is mandatory for radio-frequency (RF) ablation of typical atrial flutter (AF). CTI block can be assessed by a simplified method using two catheters and the technique of differential pacing, but long-term results in large series are poorly known. Methods: CTI RF ablation was performed in 255 consecutive patients with typical AF, using one quadripolar catheter, and the ablation catheter, in association with the technique of differential pacing. Results: Procedural success, as defined by documentation of complete bidirectional CTI block using limited activation mapping, positive differential pacing together with termination of ongoing AF, was achieved in 80% of patients. AF recurred in 37 patients (14%) over a mean follow-up period of 15 ± 9 months. Two hundred and forty-one patients (94%) were finally cured, with 1.1 procedures/patient. The recurrence rate was related to the achievement of complete CTI bidirectional block (12% vs. 29%, p = 0.01). Conclusions: Long-term results of CTI ablation, employing a simplified method using the differential pacing technique, are similar to those for the standard methods using multipolar catheters. Therefore, this technique compares favorably to other established methods for such common RF procedures, especially due to its lower cost.