Antifungal prophylaxis using fluconazole or itraconazole has been studied for many years but still no consensus has been reached regarding their safety and effectiveness. We performed a systematic meta-analysis to assess the efficacy of fluconazole compared to itraconazole in neutropenic patients with hematological malignancies. We gathered the data for our analysis from MEDLINE, EMBASE, Cochrane-controlled trials register, Cochrane Library, and Science Citation Index (1/1990 to 1/2009) searches. Risk ratio (RR) and 95% confidence intervals (CIs) were calculated using the random effect model. Nine RCTs were identified that were published in full text. Significantly, fewer patients were withdrawn from the studies due to the development of adverse effects with fluconazole prophylaxis when compared with itraconazole (RR 0.45, 95% CI 0.27–0.75, P = 0.002). There were statistically significant differences regarding fungal infections (RR 1.34, 95% CI 1.08–1.67, P = 0.009) and invasive fungal infections (RR 1.33, 95% CI 1.02–1.73, P = 0.03) between the two educations. There were no statistically significant differences regarding overall mortality (RR 0.95, 95% CI 0.77–1.17, P = 0.64), fungal-related mortality (RR 1.28, 95% CI 0.80–2.07, P = 0.31), and proven fungal infections (RR 1.38, 95% CI 0.75–2.53, P = 0.30). The analysis of published evidence reveals that itraconazole administration resulted in significantly fewer episodes of fungal infections and invasive fungal infections compared with fluconazole.