Lamivudine improves liver histology in patients with chronic hepatitis B (CHB), but its effects on portal pressure remain unknown. We evaluated the effect of lamivudine monotherapy on hepatic venous pressure gradient (HVPG) in CHB-related cirrhosis with significant portal hypertension.We studied 19 patients with cirrhosis due to HBeAg-negative CHB and HVPG ⩾10mmHg treated with oral lamivudine (100mg daily). Liver biochemistry, Child-Pugh and MELD score were determined every 3 months, alpha-fetoprotein and HBV DNA every 6 months and HVPG at baseline and at 12 months after lamivudine initiation. Diuretics, beta-blockers, antibiotics and/or endoscopic therapy were used for routine indications.At 12 months, a significant reduction was observed in ALT (p=0.001), HBV DNA (p=0.002), Child-Pugh (p=0.012) and MELD score (p=0.006). Four patients developed virological breakthrough during treatment. At 12 months, HVPG decreased in all but one patient [baseline: 14.4±3.9 and 12 months: 12.4±3.3mmHg (p=0.007)]. HVPG decreased >20% or below the 12mmHg threshold in 10 of 13 patients with baseline HVPG ⩾12mmHg. HVPG increased in a patient with hepatic flare after virological breakthrough.In conclusion, in patients with cirrhosis due to HBeAg-negative CHB, lamivudine monotherapy reduces HVPG, especially when virological suppression and biochemical remission is achieved.