Background & Aim: The goal of therapy for hepatitis B is suppression of HBV replication in a sustained manner, thus preventing further progression of the disease. In HBeAg-negative chronic hepatitis B (CHB), Lamivudine is reported to be highly effective in suppressing serum HBV-DNA to undetectable levels by PCR assays, but selection of Lamivudine-resistant mutants is the main concern. In this retrospective study, we aimed at assessing the virological and biochemical responses in HBeAg –ve CHB Egyptian patients receiving Lamivudine therapy.Patients & Methods: Routine laboratory investigations, hepatitis B markers, quantitative HBV-DNA assay by PCR and abdominal U/S were done for 140 HBeAg –ve CHB patients in (NHTMRI) in Cairo who were scheduled for Lamivudine (100 mg /day) (G I: 59 patients for 1 year, G II: 50 patients for 2 years & G III: 31 patients for 3 years).Results: Virological response occurred in76.3%, 72% & 67.7% of cases in G I, II & III respectively. Viral breakthrough rate was 0%, 12% and 25.8% of cases in G I, II & III respectively (p<0.01). The mean paired difference between pre and post treatment ALT within each single group was 18.49 ± 30.56, 12.76 ± 33.93 and 27.35 ± 54.10 U/L in group I, II and III respectively (p< 0.05 in G II & p< 0.01 in G I, III).Conclusions: Lamivudine is highly effective in HBeAg -ve CHB in suppressing serum HBV-DNA to undetectable levels by PCR assays and in ameliorating liver disease. Longer duration of Lamivudine therapy was associated with an increased rate of resistance and hence, viral breakthrough.