<p>Febrile neutropenia (FN) is a life-threatening complication requiring prompt antibiotic therapy. Increasing antimicrobial resistance threatens empirical regimen efficacy. This study characterized the microbiological spectrum, antimicrobial resistance patterns and mortality outcomes in FN patients at a tertiary hematology center in eastern India. A retrospective analysis of 1,604 FN episodes in 738 patients with hematologic diseases admitted between July 2022 and July 2024 was conducted. Microbiological isolates from blood, respiratory, urinary, and other sites underwent antimicrobial susceptibility testing using Vitek 2. Multidrug resistance (MDR) was defined as resistance to three or more antimicrobial classes. Logistic regression identified independent predictors of 30-day mortality. Among the 1,604 FN (738 patients; median age 22 years), primary diagnoses included acute myeloid leukemia (46.2%), acute lymphoblastic leukemia (34.3%), and aplastic anemia (19.5%). Blood culture positivity was 39% (445/1141). Gram-negative bacteria (GNB) predominated (67.8%) with Enterobacterales (32%), Pseudomonas (12%), and Acinetobacter (13.2%) most common. Gram-positive organisms comprised 30%. MDR prevalence was 27.8% among culture-positive patients. Class-level resistance rates included beta-lactams (43.6%), aminoglycosides (25.8%), carbapenems (26.3%), and fluoroquinolones (61.5%). The empirical cefepime-amikacin regimen achieved 84.9% coverage for culture positive episodes. Thirty-day mortality was 49.3% overall. Independent mortality predictors included age (aOR 1.03 per year), culture positivity (aOR 5.98), and respiratory infection (aOR 2.44). This study demonstrates a high antimicrobial resistance burden. The current cefepime-amikacin empirical regimen shows appropriate coverage (84.9%) for local epidemiology. Ongoing surveillance and stewardship are critical to optimize empirical therapy and improve outcomes in FN.</p>