BACKGROUND: The optimal method of detecting a lupus anticoagulant (LA) for patients taking direct factor Xa inhibitor (DFXaI) direct oral anticoagulants (DOACs) remains controversial. Methods include charcoal adsorption of the DOACs to allow testing with the activated partial thromboplastin time (APTT) and dilute Russell viper venom time (dRVVT), or use of the DFXaI-insensitive Taipan snake venom time (TSVT) and Ecarin time (ET) assays on neat plasma. OBJECTIVES: The objective was to compare the utility of APTT and dRVVT analysis following DOAC Remove against TSVT/ET on untreated plasma for LA detection in spiked plasmas and routine clinical samples for patients on DFXaIs. PATIENTS/METHODS: Various LA-negative and LA-positive samples were assayed by APTT, dRVVT, and TSVT/ET, and then separately spiked with rivaroxaban, apixaban, and edoxaban calibrators to a concentration of ~190 ng/ml and the assays repeated on spiked plasma before and after DOAC Remove treatment. Testing of 284 consecutive samples from DFXaI-anticoagulated patients by APTT/dRVVT and TSVT/ET before and after DOAC Remove treatment was undertaken. RESULTS: In the spiking model, we found that both TSVT/ET and DOAC Remove strategies generally distinguished LA-negative and LA-positive samples, but some false-positive LA results occurred. In the investigation of 284 consecutive patient samples on DFXaIs, the percentage agreement for LA detection in neat samples tested by TSVT/ET versus APTT and dRVVT after DOAC Remove treatment was 90% (Cohen kappa 0.12). CONCLUSION: Our data highlight uncertainty and disagreement for testing LA in patients on DFXaI. Further studies are required.