A recent meta-analysis, which included non-placebo open-labeled trials, showed that fluoroquinolone prophylaxis reduces mortality in neutropenic patients, whereas two recent large trials failed to show a similar benefit. Therefore, we performed a meta-analysis of randomized, blinded, placebo-controlled trials of fluoroquinolone prophylaxis in neutropenic patients. We searched several databases for relevant trials in any language. We used random effects models for pooling dichotomous data and assessed the between-study inconsistency with I2. Two investigators independently assessed the eligibility and quality of the included trials. A total of 2,721 patients were randomized in eight eligible trials. Compared to the placebo, there was a statistically non-significant but consistent decrease in mortality with fluoroquinolone prophylaxis (4.5% vs. 3.9%, relative risk (RR) 0.76, 95% confidence interval (CI) 0.54, 1.08, p=0.13, I2=0%). Significant inconsistency, however, accompanied the pooled analysis of febrile episode (39% vs. 31%, RR 0.76, 95% CI 0.55, 1.03, p=0.08, I2=96.5%). To an extent, this inconsistency was explained in the subgroup analyses by the type of patient population studied and the type of fluoroquinolone used (p for interaction ≤0.01 for both). The RR of febrile episodes for two trials of outpatients with solid tumors, including lymphomas, was RR 0.34 (95% CI 0.14, 0.80) and 0.60 (95% CI 0.33, 1.10) for two trials using levofloxacin prophylaxis. The RR in one of the two trials that used levofloxacin significantly favored the intervention, 0.76 (95% CI 0.70, 0.83). Fluoroquinolone prophylaxis reduces the risk of febrile episodes in neutropenic outpatients with solid tumors, including lymphomas, and is associated with a statistically non-significant, yet clinically important, decrease in mortality in all neutropenic patients. Prophylaxis with levofloxacin may reduce febrile episodes in neutropenic hematology patients and stem cell transplant recipients. © 2007 Springer-Verlag.