Background/Aims The results of earlier studies on determinants for the emergence of tyrosine–methionine–aspartate–aspartate (YMDD) mutants (rtM204 I/V) were controversial. The aim was to evaluate the impact of viral factors, host factors, host–viral interaction and drug factor on the emergence of rtM204 I/V. Methods 56 non-cirrhotic and 58 cirrhotic patients received lamivudine therapy for a median of 34 (12–60) months. Results rtM204 I/V emerged in 37 noncirrhotic and 36 cirrhotic patients. Stepwise logistic regression analysis showed that baseline hepatitis B e antigen (HBeAg) status [odds ratio (OR), 7.728; 95% confidental interval (CI), 2.886–12.957; P=0.0026], HBV-DNA level (OR, 3.756; 95% CI, 1.058–5.089; P=0.0202), alanine transaminase (ALT) level (OR, 6.285; 95% CI, 1.057–11.990; P=0.00246) and treatment duration (OR, 19.88; 95% CI, 8.652–31.762; P<0.0004) were independent determinants for the emergence of rtM204 I/V. Further categorical analysis and correlation test disclosed that patients with HBeAg positivity, HBV-DNA>500 pg/ml and ALT <5× upper limit of normal had significantly higher mutation rates. Conclusions HBeAg status, HBV-DNA, ALT levels and treatment duration are the major determinants for the YMDD mutation during lamivudine therapy, and should be considered in designing the therapeutic strategy.