ObjectiveTo identify, appraise and synthesise studies evaluating the downsides of wearing face masks in any setting. We also discuss potential strategies to mitigate these downsides.DesignSystematic review and meta-analysis.Data sourcesPubMed, Embase, CENTRAL and EuropePMC were searched (inception–18 May 2020), and clinical registries were searched via CENTRAL. We also did a forward–backward citation search of the included studies.Inclusion criteriaWe included randomised controlled trials and observational studies comparing face mask use to any active intervention or to control.Data extraction and analysisTwo author pairs independently screened articles for inclusion, extracted data and assessed the quality of included studies. The primary outcomes were compliance, discomforts, harms and adverse events of wearing face masks.ResultsWe screened 5471 articles, including 37 (40 references); 11 were meta-analysed. For mask wear adherence, 47% (95% CI 25% to 68%, p<0.0001), more people wore face masks in the face mask group compared with control; adherence was significantly higher (26%, 95% CI 8% to 46%, p<0.01) in the surgical/medical mask group than in N95/P2 group. The largest number of studies reported on the discomfort and irritation outcome (20 studies); fewest reported on the misuse of masks, and none reported on mask contamination or risk compensation behaviour. Risk of bias was generally high for blinding of participants and personnel and low for attrition and reporting biases.ConclusionsThere are insufficient data to quantify all of the adverse effects that might reduce the acceptability, adherence and effectiveness of face masks. New research on face masks should assess and report the harms and downsides. Urgent research is also needed on methods and designs to mitigate the downsides of face mask wearing, particularly the assessment of possible alternatives.Systematic review registrationOpen Science Framework website https://osf.io/sa6kf/ (timestamp 20-05-2020).