Objective of the present study was to describe the profile of infections in febrile neutropenia (FN) in acute leukemia and hematopoietic stem cell transplant (HSCT) with emphasis on response to therapy and outcome. In a prospective, observational single-institutional study, consecutive episodes of high-risk FN were enrolled over a 1½-year period. Uniform antibiotic policy and response criteria were used. Of the 200 episodes enrolled, acute leukemia induction comprised 40.5%, consolidation with high-dose cytarabine 22.5%, HSCT 29% (auto-HSCT 84%), and others 8% of the episodes, respectively. Microbiologically documented infections comprised 30% episodes, while bacteremia was documented in 26% episodes. Gram-negative isolates were more common (55.7%). Cefoperazone–sulbactam had the highest in vitro efficacy against Gram-negative rods. Carbapenem resistance was most prevalent among Acinetobacter spp. (80%) and Pseudomonas aeruginosa (50%). All Gram-positive cocci other than enterococci were susceptible to vancomycin, while 2/8 enterococci were resistant to it. Cefoperazone–sulbactam and amikacin were used as first-line antibiotics. Overall mortality was 8%. On multivariate analysis, mortality was associated with a nadir leukocyte count < 200/μl and an abnormal chest radiograph. Among high-risk FN patients, inspite of a high-level of resistance to antibiotics, a frontline regime containing cefoperazone–sulbactam could restrict the use of imipenem and resulted in an acceptable mortality of 8%.