The reported data regarding the effects of hypomethylating agents (HMAs) on the risk of infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all randomized controlled trials comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms.A comprehensive search was conducted until February 2018. Two reviewers appraised the quality of the trials and the extracted data. The primary outcome was grade 3/4 infections. The secondary outcomes included febrile neutropenia, fever of unknown origin, grade 3/4 neutropenia, infection-related mortality, and all-cause mortality. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool the data unless significant heterogeneity was present, in which case a random-effects model was used.We identified 9 trials reported from 2002 to 2016 and randomizing 2184 patients. HMAs were associated with an increase in grade 3/4 infections compared with the comparator (RR, 1.30; 95% CI, 1.02-1.66). This was true for the subgroup of patients aged >60 years (RR, 1.19; 95% CI, 1.01-1.39). In addition, HMAs resulted in an increase in the rate of fever of unknown origin and neutropenia (RR, 1.48; 95% CI, 1.15-1.92; RR, 1.48; 95% CI, 1.22-1.78, respectively). Although no difference was found in the incidence of fatal infections (RR, 1.44; 95% CI, 0.72 to 2.89), treatment with HMA reduced the incidence of all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88).Treatment with HMAs was associated with an increase in the grade 3/4 infection rate.