AIM: The bisoprolol transdermal patch is a newly developed beta-blocker designed to deliver its pharmaceutical ingredient through the skin surface. We aimed to compare the bisoprolol transdermal patch and bisoprolol fumarate tablet using the heart rate variability (HRV). METHOD: Eligible hypertensive patients received a 2-week administration with a 2.5 mg bisoprolol fumarate tablet, followed by 24-hour Holter monitoring. The tablet was then switched to a 4 mg bisoprolol transdermal patch, and after 2 weeks of its administration, the Holter monitoring was repeated. Both drugs were given once daily. Endpoint was any alteration in the HRV caused by a change in the administration route for bisoprolol. RESULTS: There was no difference in the 24-hour time-domain and frequency-domain HRV measurements before and after the drug switching among patients recruited (N = 30). However, the switching significantly altered the time-course curves of the hourly HRV measurements, including the mean normal-to-normal (NN) interval (P = .004), standard deviation of the NN index (P < .001), high frequency component (P = .01), and low frequency component (P = .003). Those alternations were attributed to the slower heart rate and more decreased short-term autonomic fluctuation resulting from the administration of the bisoprolol transdermal patch, which were observed later than 12 hours after the drug initiation. No adverse events were noted throughout the study period. CONCLUSION: The pattern of the autonomic modulation may vary depending on either a transdermal or oral administration even though an equivalent dose of bisoprolol is given.