Earlier clinical studies have reported an ALT flare greater than 10 times the upper limit of normal in some patients with chronic hepatitis B when their lamivudine (LAM) treatment was switched to adefovir (ADV) therapy. The current study compared the safety of switching directly to ADV versus overlapping LAM and ADV for 3 months followed by ADV monotherapy. Patients with chronic hepatitis B receiving LAM therapy for ≥6 months were eligible for the study regardless of the presence of LAM resistance, HBeAg status or serum ALT levels. Eighteen patients (13 males) were randomized to direct switch to ADV and 17 patients (10 males) to overlap. HBV-DNA, ALT, albumin, and total bilirubin were assayed at baseline, 3, 6, 9, and 12 months. Study drugs were discontinued at the end of 12 months with the follow up at 3 and 6 months. The decision to continue antiviral therapy was made at the discretion of the investigator. Baseline ALT levels were similar between the direct switch and overlap group: median ALT (U/L) was 44.0 (16–266) and 33.0 (19–367) for direct switch for overlap group, respectively (P = 0.42). No ALT flare was noted at 3 months in either group: median ALT decreased from 44.0 to 34.5 U/L in the direct switch group, and from 33.0 to 23.0 in the overlap group. Furthermore, no patient in either group exhibited ALT flare throughout the 12 months. This study did not show an ALT flare during switch to ADV at 3 months or at any time later. J. Med. Virol. 82:1489–1493, 2010. © 2010 Wiley-Liss, Inc.