ABSTRACT: Background:We aimed to systematically assess a possible association of tofacitinib therapy with cardiovascular events (CVEs) and all-cause mortality. Methods:Systematic searches of PubMed, Embase, and Cochrane Library were conducted from inception through March 2019. Randomized controlled trials in patients with immune-mediated inflammatory diseases (IMIDs) reporting safety data were included. Included studies compared tofacitinib with placebo or 5?mg tofacitinib with 10?mg tofacitinib. The primary and secondary outcome measures were all CVEs [major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs)] and all-cause mortality. Results:29 studies randomizing 13,611 patients were included. Compared with placebo, there was no significant increased risk of all CVEs (OR?=?1.07, 95% CI 0.49-2.34), MACEs (OR 1.54, 95% CI 0.42-5.59), or all-cause mortality (OR?=?1.13, 95% CI 0.26-4.95), but a decreased rate of VTEs (OR 0.03, 95% CI 0.00-0.21) in patients with IMIDs initiating tofacitinib. Meanwhile, paired comparison showed 10?mg tofacitinib twice daily was associated with a significantly lower incidence of all CVEs (OR?=?0.56, 95% CI 0.33-0.96), MACEs (OR?=?0.48, 95% CI 0.22-1.05), or all-cause mortality (OR?=?0.47, 95% CI 0.19-1.17), but a trend toward an increase in VTEs risk (OR?=?1.47, 95% CI 0.25-8.50), compared with the 5?mg regimen. Conclusion:Compared with placebo, there was no augmented risk of CVEs and all-cause mortality in patients with IMIDs following tofacitinib treatment in a short-term perspective, whereas 10?mg twice daily tofacitinib appeared to be associated with reduction in cardiovascular and all-cause mortality risks, except VTEs, relative to the 5?mg twice daily dose. Long-term studies and postmarketing risk monitoring are increasingly needed to develop a better understanding.