The purpose of this study was to identify the frequency of bacterial infections and side effects and resistance to ciprofloxacin prophylaxis during febrile neutropenia (FEN) in children with acute leukemia. Our study included 80 patients with acute lymphoblastic leukemia (ALL) who received the ALL-BFM 95 protocol and 20 patients with acute myeloblastic leukemia (AML) who received the AML-MRC 12 protocol. When the neutrophil count began falling below 500/µL, all patients were started on ciprofloxacin prophylaxis. The clinical and microbiological documented bacterial infections as well as ciprofloxacin side effects and resistance were also recorded. In total, 195 FEN episodes in ALL and 72 FEN episodes in AML were found. The rate of FEN episodes per 30 days and 1000 days of neutropenia was significantly higher in AML than in ALL (p<0.05). In children with ALL, the rate of FEN ranged from 36% to 68% in all phases except the consolidation phase, whereas, in children with AML, the rate of FEN ranged from 75% to 95% in all chemotherapy phases. Gram (+) agents were identified in the majority (60-68%) of children, but the Viridans group Streptococci were documented in only three. Positive surveillance bacterial cultures were uncommon. Quinolone resistance was 25-30% at the start of treatment and reduced to 10-13% toward the end of the treatment in both leukemia groups. Most of the quinolone-related side effects including tendinopathy or tendon rupture were not observed. Our data suggest that ciprofloxacin prophylaxis may be required in children with AML who had a high rate of FEN in all chemotherapy phases, but only during the induction and intensification phases in children with ALL. In those patients, quinolone side effects and resistance should be periodically monitored. Routine surveillance of bacterial cultures has no further advantage in reducing FEN attacks.