Abstract Background Infections by influenza viruses place a heavy burden on public health and economies worldwide. Although vaccines are the best weapons against influenza, antiviral drugs could offer an opportunity to alleviate the burden of influenza. Since omeprazole family compounds block the “proton pump”, we hypothesized that they could interfere with the mechanism of fusion of the virus envelope and endosomal membrane, thereby hindering the M2 proton pump mechanism of influenza viruses. Methods A matched case-control study was performed in 2010-2011 in Italy. Cases were subjects aged over 18 years with a diagnosis of Influenza-like Illness (ILI); 254 case-control pairs were recruited. A multivariable conditional logistic regression analysis was used to assess the association between the prevention of ILI and the administration of omeprazole family compounds. The interaction between omeprazole family compounds and influenza vaccination was also examined. Results After control for potential confounders, subjects treated with omeprazole family compounds displayed a lower risk of catching ILI (OR adj  = 0.29, 95% CI: 0.15-0.52). The risk of ILI in unvaccinated non-OFC users was about six times than that in vaccinated OFC users. Conclusions Although confirmation is necessary, these results suggest that omeprazole family compounds could be profitably used in the prevention of ILI.