Taking nucleoside/nucleotide analogs is a major antiviral therapy for chronic hepatitis B infection. The problem with this treatment is the selection for drug-resistant mutants. Currently, identification of genotypic drug resistance is conducted by molecular cloning sequenced by the Sanger method. However, this methodology is complicated and time-consuming. These limitations can be overcome by deep sequencing technology. Therefore, we performed sequential analysis of the frequency of drug resistance in one individual, who was treated with lamivudine on-and-off therapy for 2 years, by deep sequencing. The lamivudine-resistant mutations at rtL180M and rtM204V and the entecavir-resistant mutation at rtT184L were detected in the first subject. The lamivudine- and entecavir-resistant strain was still detected in the last subject. However, in the deep sequencing analysis, rt180 of the first subject showed a mixture in 76.9% of the methionine and in 23.1% of the leucine, and rt204 also showed a mixture in 69.0% of the valine and 29.8% of the isoleucine. During the treatment, the ratio of resistant mutations increased. At rt184, the resistant variants were detectable in 58.7% of the sequence, with the replacement of leucine by the wild-type threonine in the first subject. Gradually, entecavir-resistant variants increased in 82.3% of the leucine in the last subject. In conclusion, we demonstrated the amino acid substitutions of the serial nucleoside/nucleotide analog resistants. We revealed that drug-resistant mutants appear unchanged at first glance, but actually there are low-abundant mutations that may develop drug resistance against nucleoside/nucleotide analogs through the selection of dominant mutations.