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Several studies suggest that neuraminidase inhibitors (NIs) can reduce the duration of influenza symptoms. However, data regarding their effectiveness in reducing influenza complications are scarce.We evaluated the effectiveness of NIs in reducing influenza complications and mortality of patients with seasonal influenza, by performing a meta-analysis of randomized controlled trials (RCTs), retrieved from PubMed, Cochrane Central Register of Controlled Trials and Scopus databases, comparing NIs with placebo.Eleven RCTs (10 double-blind) were included; 8 involved adults/adolescents. In total, 5315 patients were included; 3491 (65.7%) with confirmed infection. Total influenza-related complications were significantly less likely in otherwise healthy patients with confirmed influenza infection that were treated with NIs versus placebo [7 RCTs, 2621 patients, risk ratio (RR) = 0.74, 95% confidence interval (CI) = 0.58–0.95] This finding was more pronounced in high-risk patients [4 RCTs, 475 patients, RR = 0.37, 95% CI = 0.24–0.59]; P < 0.01 for the χ2 test for subgroup differences. In the comparisons regarding individual complications, a trend in favour of NIs was observed. Acute otitis media was significantly less likely in patients with confirmed influenza infection treated with NIs versus placebo (3 RCTs, 1124 patients, RR = 0.50, 95% CI = 0.30–0.85). No differences were found in the comparisons regarding the safety outcomes. No deaths were observed in trials that reported on mortality.NIs seem to be effective in reducing total influenza-related complications in otherwise healthy and high-risk patients, and have an acceptable safety profile. However, RCTs providing separate data for mild to serious complications and detailed reporting of adverse events and mortality are needed.