OBJECTIVE To evaluate the efficacy and safety of alteplase infusions and alteplase local instillations (dwells) to clear partially occluded central venous catheters in critically ill children. DESIGN Retrospective study. SETTING PICU in a single, tertiary care, academic children's hospital. PATIENTS Retrospective review of the medical records of all critically ill pediatric patients less than 18 years old who received an alteplase infusion or dwell as the treatment for a partial central venous catheter occlusion. The typical infusion regimen was to administer 0.1 mg/kg of body weight (maximum, 2 mg/dose) of alteplase in 25 mL of 0.9% sodium chloride over 3 hours. The standard dwell was to administer and aspirate alteplase in a 1 mg/mL concentration as a fixed dose as ordered by the prescriber (maximum, 2 mg/dose). Efficacy was defined as documentation of positive blood return from the catheter. Radiology reports, nursing and physician documentation, and laboratory values were reviewed to assess for bleeding events. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS One hundred fifty occlusion events were included for analysis. Overall, 72 of 84 alteplase infusions (86%) and 53 of 66 alteplase dwells (80%) resulted in resolution of the lumen occlusion event as documented by positive blood return from the catheter after a maximum of two doses (p = 0.39). One major bleeding event occurred in each arm; both were deemed unlikely related to alteplase. CONCLUSIONS Alteplase infusions to clear partially occluded central venous catheters appear to be as efficacious as alteplase dwells in critically ill children. In occlusions treated with an infusion, more occlusions resolved in older and larger patients and in patients with catheters in place less than 7 days. In occlusions treated with a dwell, more occlusions resolved in smaller catheters. The safety profile for both infusions and dwells was acceptable for the pediatric critically ill population.