Background: There are two conventional modalities used to perform therapeutic plasma exchange (TPE): centrifuge TPE (cTPE) or membrane TPE (mTPE). There is limited data on complications with mTPE. Objective: We sought to better understand the patient and machine complications of mTPE compared to cTPE. We hypothesize that our protocol for mTPE using heparin anticoagulation is well-tolerated. Methods: In this retrospective cohort study of children <21 years of age, we evaluated differences in patient and machine characteristics and complications between cTPE (with citrate anticoagulation) vs mTPE (with heparin anticoagulation). Results: Of the 105 patients who met inclusion/exclusion criteria, 63 received cTPE and 42 mTPE via Prismaflex. Those who used mTPE were younger (4.8 ± 2.8 years vs 15.2 ± 3.7 years, P =.0001) and weighed less (19.5 ± 10.6 vs 71.7 ± 28.5 kg, P =.0001). There were no significant differences in patient-related complications or indications for TPE between the two modalities. Of the 1031 therapies performed,1003 therapies were analyzed (646 using cTPE and 357 using mTPE) due to exclusion criteria. No significant difference in patient complications were detected between groups. Machine-related complications were infrequent in both approaches. More circuits clotted during mTPE than during cTPE (6.7% [24/357] vs 0% [0/646]; P < 0.001). Conclusion: Although we use mTPE in smaller children, we showed low rates of complications that were not statistically different from cTPE performed in older children. While the overall rate of circuit clotting using mTPE was low, it occurred more commonly than with cTPE.