OBJECTIVES: Nucleoside/Nucleotide analogues (NAs) are used for the treatment of chronic hepatitis B virus infection (CHB), but the treatment may fail due to several factors, including viral resistance. Resistance pattern in Egyptian patients is still unknown; hence, the aim of the current study was to evaluate the prevalence of NAs resistance and its potential predictors in Egyptian patients with CHB. METHODS: A retrospective, cross sectional study on CHB Egyptian patients on NAs, including lamivudine, tenofovir, lamivudine/ adefovir combination, and entecavir. The study was conducted at the National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt. During the period of April, 2018 till June, 2018, all CHB patient files were reviewed for the NAs interventions used and the 4 years cumulative incidence of resistance. The cumulative incidence of resistance was defined as at least a 10 fold increase in Hepatitis B Virus DNA level from Nadir after initial response (repeated after a month to confirm that the increase is not by chance). RESULTS: Data from 339 CHB treatment adherent patients were included. The majority (n=217) were on lamivudine monotherapy with a resistance of 35%. In tenofovir interventions (n=90), resistance was 1.1%. In lamivudine + adefovir interventions (n=16), resistance was 93.8% which may be attributed to the unavailability of this combination. In entecavir intervention (n=16), resistance was 25%. As majority of the interventions (64%) were lamivudine monotherapy, demographic and biochemical data were analyzed in a regression model to predict risk factors associated with lamivudine resistance; independent risk factor of resistance was HBeAg positive (p=0.014). CONCLUSIONS: Lamivudine was the most frequently prescribed NA for the treatment of CHB in Egypt, with a 4 year cumulative resistance of 35% especially in those with HBeAg positive status. Tenofovir was the agent with the least resistance among the tested NAs interventions in CHB Egyptian patients.