Background: There are limited data about the mortality and morbidity of patients with HBV flare related to immunosuppressive treatments (IST) in the third-generation antivirals era. Herein, we performed a multi-centric study in patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) and evaluated their clinical course. Methods: The study group included patients who were referred to gastroenterology or infectious disease specialists at eight different hospitals in Turkey. HBV flare was defined as at least a threefold elevation in alanine aminotransferase (ALT) levels above the upper limit of normal range. The demographic data, IST protocol, virological markers, liver tests, international normalized ratio (INR), HBV DNA, reactivation risk profile according to AGA guideline, MELD and MELD-Na scores were retrospectively evaluated. The primary aim of the study was to determine the liver-related mortality, including transplantation, at 12 weeks and factors predicting it. Secondary aims were to compare ETV and TDF with respect to mortality and time to ALT, bilirubin normalization and HBV DNA undetectability. Results: The study group included 40 patients (29 males, mean age: 57 +/- 12 years). Twenty-five patients (62.5%) had a high risk of reactivation. Twenty-six patients received TDF and 14 patients received ETV treatment. Eight (20%) patients developed acute liver failure and one patient (2.5%) underwent living donor liver transplantation. Seven patients died due to liver-related complications, revealing a mortality rate of 17.5%. In multivariate analysis, total bilirubin levels at the onset, ALT levels and delta-MELD score at the first week were the independent risk factors for liver related mortality (HR: 1.222, 1.003, 1.253 and 95% CI: 1.096, 1.362; 1.001, 1.004 and 1.065, 1.470, respectively). There was no significant difference between the TDF and ETV groups with respect to time to normalize ALT and bilirubin levels, HBV DNA undetectability and mortality rates (16% and 21.4%, respectively). Conclusions: HBV flare associated with 1ST has a high mortality in the third-generation antivirals era. High total bilirubin at the onset and high ALT and delta-MELD score at the first week predict poor prognosis.