In patients with congestive heart failure, abnormal heart rate variability is a predictor of total mortality and sudden cardiac death. Drugs that improve heart rate variability may have a potential role for improving the survival among these patients. The effects of clonidine were studied in 24 patients with congestive heart failure, sinus rhythm, a left ventricular ejection fraction <0.40, and systolic blood pressure > 115 mm Hg. A 6-minute corridor walk test and 24-hour Holter monitoring were performed before and 42+/-24 days after initiation of clonidine therapy (Catapres-TTS patch, mean dose: 0.33+/-0.21 mg). Changes in other medications used at baseline were not allowed. One patient died suddenly. Two patients did not complete the protocol due to worsening congestive heart failure, which required changes in medications, 1 patient discontinued due to hypotension, and 2 for personal reasons. Among the 18 patients who completed the protocol, the mean RR interval of sinus beats increased from 760+/-106 to 822+/-125 ms (p=0.001) and the distance covered during the 6-minute walk test increased from 1,148+/-277 to 1,255+/-359 feet (p=0.042). Systolic blood pressure decreased from 139+/-15 to 119+/-10 mm Hg (p <0.0001). The following increases were noted in the heart rate variability measurements: high-frequency power in 0.15 to 0.40 Hz: 4.58+/-1.07 to 4.94+/-1.17 In (ms), p=0.002; SD: 47.0+/-16.9 to 52.5+/-18.4 ms, p=0.034; SD of the mean of all RR intervals in 24 hours: 116+/-94 to 130+/-19 ms, p=0.033; SD of all 5-minute mean RR intervals: 106+/-44 to 124+/-66 ms, p=0.042; root-mean square of difference of successive RR intervals: 28.8+/-10.7 to 34.1+/-14.2 ms, p=0.017. Clonidine improves heart rate variability in the patients with congestive heart failure by increasing the parasympathetic tone. It is well tolerated by most patients with heart failure and may have a beneficial effect on exercise capacity.