Entecavir (ETV) is widely used in the treatment of hepatitis B, but there are only a few reports about entecavir-associated thrombocytopenia, and it is considered as an immediate response and inappropriate to continue the treatment with other nucleoside analogues. Now, we report the third case, and this case was delayed response and we switched to treatment with tenofovir (TDF). There was a 66-year-old female who was infected with hepatitis B virus (HBV). Her platelet count decreased from 111*109/L to 3*109/L and was prone to gum bleeding and skin ecchymosis after she received ETV treatment for 88 days. As a treatment option, ETV was replaced by TDF immediately, frequent platelets transfusions and thrombopoietin were applied for several days, daily prednisone of 50 mg was concomitantly taken, and then platelet count improved after 10 days. She was diagnosed with entecavir-associated thrombocytopenia after analysis of the temporal relationship and exclusion of other causes of thrombocytopenia by blood and bone marrow examinations. Our case suggested that the platelet count should be monitored regularly in patients during ETV treatment, and it may be a feasible option to choose TDF to maintain antiviral treatment when entecavir-associated thrombocytopenia occurs.