Introduction: The aim of this study was to compare the effect of ramipril/canrenone versus ramipril/hydrochlorothiazide (HCTZ) combination on atrial fibrillation (AF) recurrence in type 2 diabetic hypertensives with and without cardiac autonomic neuropathy (CAN). Material and methods: A total of 289 hypertensive type 2 diabetic patients, 95 with CAN, in sinus rhythm but with at least two episodes of AF in the previous 6 months were randomized to ramipril 5 mg plus canrenone 50 mg (titrated to 10/100 mg) or to ramipril 5 mg plus HCTZ 12.5 mg (titrated to 10/25 mg) or to amlodipine 5 mg (titrated to 10 mg) for 1 year. Clinic blood pressure (BP) and a 24-h ECG were evaluated monthly. Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. Serum procollagen type I carboxy-terminal peptide (PIP) and carboxy-terminal telopeptide of collagen type I (CITP) were evaluated before and after each treatment period. Results: Blood pressure was similarly and significantly reduced by all treatments. A total of 51% of patients with amlodipine had a recurrence of AF, as did 31% of patients with ramipril/HCTZ (p < 0.05 vs. amlodipine) and 13% of patients with ramipril/canrenone (p < 0.01 vs. amlodipine and p < 0.05 vs. ramipril/HCTZ). A similar trend was found in diabetic patients with CAN. Both combinations reduced PIP and increased CITP, but the effects of ramipril/canrenone were significantly more marked. Conclusions: These findings suggest that in type 2 diabetic hypertensives, ramipril/canrenone treatment was more effective than ramipril/HCTZ in reducing AF recurrence. This could be related to the greater improvement in cardiac fibrosis.