BACKGROUND: Phlebitis is an important complication occurring in patients with peripheral intravascular catheters (PIVCs). The risk factors for phlebitis in the intensive care unit (ICU) was examined. METHODS: A secondary analysis of a prospective multicenter cohort study was conducted, involving 23 ICUs in Japan-the AMOR-VENUS study. Consecutive patients aged ≥ 18 years admitted to the ICU with newly inserted PIVCs after ICU admission were enrolled. Characteristics of the ICU, patients, PIVCs, and the drugs administered via PIVCs were recorded. A marginal Cox regression model was used to identify the risk factors associated with phlebitis. RESULTS: A total of 2741 consecutive patients from 23 ICUs were reviewed for eligibility, resulting in 1359 patients and 3429 PIVCs being included in the analysis population. The median dwell time was 46.2 h (95% confidence interval [CI], 21.3-82.9). Phlebitis occurred in 9.1% (95% CI, 8.2-10.1%) of catheters (3.5 cases/100 catheter days). The multivariate analysis revealed that the only factors that increased the risk of developing phlebitis were drugs administered intravenously. This study included 26 drugs, and 4 were associated with increased phlebitis: nicardipine (HR, 1.85; 95% CI, 1.29-2.66), noradrenaline (HR, 2.42; 95% CI, 1.40-4.20), amiodarone (HR, 3.67; 95% CI, 1.75-7.71) and levetiracetam (HR, 5.65; 95% CI, 2.80-11.4). Alternatively, factors significantly associated with a reduced risk of phlebitis were: standardized drug administration measures in the ICU (HR, 0.35; 95% CI, 0.17-0.76), 30≤ BMI (HR, 0.43; 95% CI, 0.20-0.95), catheter inserted by a doctor as nurse reference (HR, 0.55; 95% CI, 0.32-0.94), and upper arm insertion site as forearm reference (HR, 0.52; 95% CI, 0.32-0.85). The nitroglycerin was associated with a reduced phlebitis risk (HR, 0.22; 95% CI, 0.05-0.92). CONCLUSION: Various factors are involved in the development of phlebitis caused by PIVCs in critically ill patients, including institutional, patient, catheter, and drug-induced factors, indicating the need for appropriate device selection or models of care in the ICU. TRIAL REGISTRATION: UMIN-CTR, the Japanese clinical trial registry (registration number: UMIN000028019, July 1, 2017).