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Abstract Objective Angioplasty is a fundamental treatment for atherosclerotic disease and may be performed as the sole therapy in small vessel disease. However, the ideal duration of balloon inflation has not yet been identified. Our study investigated whether prolonged inflation of at least 1-min duration, when compared with brief inflation, affects residual stenosis after arterial angioplasty. Data sources and methods Two independent reviewers conducted a systematic review of EMBASE, MEDLINE, CENTRAL, trial registries and grey literature, using pre-specified search syntax. Data abstraction and quantitative analysis was performed independently, according to pre-specified criteria. The primary outcome was residual stenosis after initial angioplasty, in addition to other pre-specific clinical and radiographic outcomes. All analyses were stratified by coronary, cerebrovascular, and peripheral territory. The study protocol is published and registered on PROSPERO (CRD42018092702). Results Six relevant articles were identified, of which one investigated peripheral vascular angioplasty and five investigated coronary artery angioplasty, encompassing 1496 procedures. The studies were at moderate risk of bias. Minimal heterogeneity within coronary studies allowed for subgroup meta-analysis. Prolonged inflation was significantly associated with lower risk of residual stenosis post-inflation in the pooled coronary trials (RR 1.76 [95% CI 1.46–2.12], I2 = 0%, p