AIM: We set to determine factors that determine clinical severity after the development of resistance.METHODS: Thirty-five Asian patients with genotypic lamivudine resistance were analyzed in three groups:13/35 (37%) were non-cirrhotics with normal pre-treatment ALT (Group IA), 12/35 (34%) were non-cirrhotics with elevated pre-treatment ALT (Group IB), and 10/35 (29%)were cirrhotics (Group Ⅱ). Patients were followed for a median of 98 wk (range 26-220) after the emergence of genotypic resistance.RESULTS: Group IA patients tended to retain normal ALT.Group IB patients showed initial improvement of ALT with lamivudine but 9/12 patients (75%) developed abnormal ALT subsequently. On follow-up however, this persisted in only 33%. Group Ⅱ patients also showed improvement while on treatment, but they deteriorated with the emergence of resistance with 30% death from decompensated liver disease. Pretreatment ALT levels and CPT score (in the cirrhotic group) were predictive of clinical resistance and correlated with peak ALT levels and CPT score.CONCLUSION: The phenotype of lamivudine-resistant HBV correlated with the pretreatment phenotype. The clinical course was generally benign in non-cirrhotics.However, cirrhotics had a high risk of progression and death (30%) with the development of lamivudine resistance.