BACKGROUND Almost 70% of hospitalized patients require a peripheral intravenous catheter (PIV), yet up to 69% of PIVs fail prior to completion of therapy. OBJECTIVE To identify risk factors associated with PIV failure. DESIGN A single center, prospective, cohort study. SETTING Medical and surgical wards of a tertiary hospital located in Queensland, Australia. PARTICIPANTS Adult patients requiring a PIV. MEASUREMENTS Demographic, clinical, and potential PIV risk factors were collected. Failure occurred if the catheter had complications at removal. RESULTS We recruited 1000 patients. Catheter failure occurred in 512 (32%) of 1578 PIVs. Occlusion/infiltration risk factors included intravenous (IV) flucloxacillin (hazard ratio HR, 1.98; 95% confidence interval CI, 1.19‐3.31), 22‐gauge PIVs (HR, 1.43; 95% CI, 1.02‐2.00), and female patients (HR, 1.48; 95% CI, 1.10‐2.00). Phlebitis was associated with female patients (HR, 1.81; 95% CI, 1.40‐2.35), bruised insertion sites (HR, 2.16; 95% CI, 1.26‐3.71), IV flucloxacillin (HR, 2.01; 95% CI, 1.26‐3.21), and dominant side insertion (HR, 1.39; 95% CI, 1.09‐1.77). Dislodgement risks were a paramedic insertion (HR, 1.78; 95% CI, 1.03‐3.06). Each increase by 1 in the average number of daily PIV accesses was associated (HR 1.11, 95% CI 1.03‐1.20)–(HR 1.14, 95% CI 1.08‐1.21) with occlusion/infiltration, phlebitis and dislodgement. Additional securement products were associated with less (HR 0.32, 95% CI 0.22‐0.46)–(HR 0.63, 95% CI 0.48‐0.82) occlusion/infiltration, phlebitis and dislodgement. CONCLUSION Modifiable risk factors should inform education and inserter skill development to reduce the currently high rate of PIV failure.