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The landscape of HBV prophylaxis management in hepatitis B core antibody (HBcAb) positive patients has changed significantly following the publication of the latest international guidelines. These guidelines have led to new recommendations for the use of entecavir (ETV) or tenofovir (TDF) as preferred agents, given lamivudine’s (3TC) high resistance rates (20–30% at 1–2 years vs approximately 1% at 5 years with ETV).This single-center retrospective study aimed to evaluate the real-world effectiveness of 3TC prophylaxis in preventing HBV reactivation (HBVr) in HBcAb positive hematologic patients undergoing chemotherapy and/or immunotherapy. The secondary aims were to identify clinical and virological predictors of treatment failure and assess the safety profile of 3TC in this population. These findings may clarify lamivudine’s residual role in current practice and inform optimal HBV prophylaxis strategies in hematologic patients.We analyzed data from a prospectively maintained database including 380 hematologic patients diagnosed and followed at SC Ematologia IRCCS Policlinico San Matteo. Eligible patients were those who received immunosuppressive therapy and anti-HBV prophylaxis with 3TC between 2002 and 2025 administered 2 weeks before haematologic therapy start and continued for 18 months after its completion. The risk of HBVr was stratified according to the latest European Association for the Study of the Liver (EASL) guidelines.The patients were stratified into 3 HBVr risk groups (table 1): high risk (301/380), intermediate risk (77/380), and low risk (2/380). Overall, 10/380 patients (2.6%) experienced HBVr during follow-up. Among these, 6/10 patients were in the high-risk group and 4/10 were in the intermediate-risk group. Among 380 patients included in the study, 8 were HBsAg positive and 367 were HBsAg negative; data were not available for 5 patients. HBVr occurred in 1 of 8 HBsAg-positive patients (12.5%) and in 9 of 367 HBsAg-negative patients (2.45%), corresponding to an approximately 5-fold higher risk in HBsAg-positive individuals (95% CI: 0.73–35.6). Regarding steroid therapy, HBVr was observed in 1 of 9 steroid-treated patients (11.1%) compared with 9 of 364 patients (2.5%) who did not receive steroids. Although it was estimated an increased risk among steroid-treated patients, the association was not statistically significant, likely due to the small sample size and limited number of events. Following reactivation, 7 patients (70%) were treated with ETV, 2 patients (20%) with TDF, and 1 patient (10%) continued 3TC. All patients achieved complete virological response, defined as undetectable HBVDNA.In this study, 3TC prophylaxis was safe and associated with a low rate of HBVr in HBcAb positive hematologic patients receiving immunosuppressive therapy. Despite guideline preferences for newer antivirals, 3TC appears to remain a reasonable and well-tolerated option, though further studies are needed to confirm its effectiveness.Abstract P106 Table 1Baseline patients’ characteristics