Background: Several randomized controlled trials ( RCT s) have already shown that paclitaxel‐coated balloons and stents significantly reduce the rates of vessel restenosis and target lesion revascularization after lower extremity interventions. Methods and Results: A systematic review and meta‐analysis of RCT s investigating paclitaxel‐coated devices in the femoral and/or popliteal arteries was performed. The primary safety measure was all‐cause patient death. Risk ratios and risk differences were pooled with a random effects model. In all, 28 RCT s with 4663 patients (89% intermittent claudication) were analyzed. All‐cause patient death at 1 year (28 RCT s with 4432 cases) was similar between paclitaxel‐coated devices and control arms (2.3% versus 2.3% crude risk of death; risk ratio, 1.08; 95% CI, 0.72–1.61). All‐cause death at 2 years (12 RCT s with 2316 cases) was significantly increased in the case of paclitaxel versus control (7.2% versus 3.8% crude risk of death; risk ratio, 1.68; 95% CI, 1.15–2.47; —number‐needed‐to‐harm, 29 patients [95% CI , 19–59]). All‐cause death up to 5 years (3 RCT s with 863 cases) increased further in the case of paclitaxel (14.7% versus 8.1% crude risk of death; risk ratio, 1.93; 95% CI , 1.27–2.93; —number‐needed‐to‐harm, 14 patients [95% CI , 9–32]). Meta‐regression showed a significant relationship between exposure to paclitaxel (dose‐time product) and absolute risk of death (0.4±0.1% excess risk of death per paclitaxel mg‐year; P <0.001). Trial sequential analysis excluded false‐positive findings with 99% certainty (2‐sided α, 1.0%). Conclusions: There is increased risk of death following application of paclitaxel‐coated balloons and stents in the femoropopliteal artery of the lower limbs. Further investigations are urgently warranted. Clinical Trial Registration: URL : www.crd.york.ac.uk/PROSPERO . Unique identifier: CRD 42018099447.