ABSTRACTVesicular monoamine transporter type 2 (VMAT2) inhibitors may be an effective therapy for chronic tic disorders (CTD), including Tourette syndrome (TS), but there has not been a meta‐analysis compiling available evidence from randomized controlled trials (RCTs). We performed a systematic review and meta‐analysis to evaluate the efficacy, acceptability, and tolerability of VMAT2 inhibitors for CTD/TS. PubMed, CENTRAL, and Embase were searched for double‐blinded RCTs of VMAT2 inhibitors versus placebo for the treatment of CTD/TS. Change in tic severity measured by the Yale Global Tic Severity Scale (efficacy) and rates of discontinuation attributed to adverse effects (tolerability) or all causes (acceptability) were extracted closest to 12 weeks. Mean difference (MD) and odds ratio (OR) were the effect size indexes for efficacy and acceptability/tolerability, respectively. Data were pooled through random‐effects meta‐analysis weighted by inverse variance. Five RCTs involving eight comparisons were included. Meta‐analysis found a nonsignificant effect on efficacy (k = 8; N = 583; MD = −0.71; 95% confidence interval [CI], −1.93 to 0.50; P = 0.24), and there was certainty that the true effect is nonclinically meaningful (high quality of evidence). Meta‐analysis found decreased tolerability (k = 7; N = 626; OR = 2.67; 95% CI, 1.21–5.92; P = 0.01) and decreased acceptability (k = 8; N = 626; OR = 1.90; 95% CI, 1.14–3.18; P = 0.01), although those comparisons were limited because of the relatively small number of events across trials. Meta‐analyses did not support the efficacy of VMAT2 inhibitors in the short‐term treatment of tic disorders and suggested no clinically meaningful effect of these agents on tic symptoms. © 2022 International Parkinson and Movement Disorder Society