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Background Lamivudine (3TC)-resistant chronic hepatitis B patients demonstrated a higher rate of adefovir dipivoxil (ADV) resistance compared with nucleoside-naive patients. This study describes ADV mutation patterns in 3TC-resistant patients treated with ADV+3TC or ADV monotherapy, investigating whether mutations selected during 3TC therapy predispose to ADV resistance. Risk factors for ADV resistance were also evaluated. Methods A total of 60 3TC-experienced patients were treated with (or switched to) ADV monotherapy (30 patients) or ADV+3TC combination therapy (30 patients), and followed for at least 12 months. In all patients the hepatitis B virus reverse transcriptase (RT) region was amplified and directly sequenced before initiating ADV. The RT sequence was reevaluated for virological breakthrough patients and phenotypic analysis was performed for several patients. Results In total, 14 (23%) patients showed virological breakthrough (10/30 on ADV monotherapy and 4/30 on ADV+3TC). ADV resistance mutations (rtA181V/T and rtN236T) were detected alone or in combination for 11/14 patients, whereas novel substitutions were present in 3 patients. Before ADV treatment, apart from 3TC resistance signature mutations, additional changes were found, including the rtA181T mutation, which was already present in 2/14 ADV-resistant patients. Conclusions Although most patients showed virological breakthrough because of the well known rtA181V/T and rtN236T substitutions, more complex patterns were also found. ADV monotherapy, dose reduction and suboptimal virological response after 48 weeks of therapy were significantly associated with ADV resistance.