As the loss of HBsAg during treatment of chronic hepatitis delta (CHD) is mandatory for definitive clearance and durable response, the optimal target of therapy should be complete response (CR), defined as loss of HDV RNA and HBsAg, plus development of anti-HBs. The optimal treatment duration of CHD is not well established. We present 2 cases of patients with CHD cirrhosis who were treated with prolonged Peg-IFNα-2a + tenofovir disoproxil fumarate until HBsAg loss, and who achieved CR after 46 and 55 months of treatment respectively. A personalized approach and prolonged treatment duration determined by HBsAg loss may increase the likelihood of CR in CHD.