Abstract Objectives Antiphospholipid syndrome (APS) can be complicated by thrombosis in the presence of laboratory evidence of persistent antiphospholipid antibodies, usually in the form of a LAC. The diagnostic criteria for APS/LAC require persistent prolongation of two phospholipid-dependent clotting assays, most often the dRVVT and a thromboplastin-based phospholipid-neutralization (PN) assay. When there is discrepancy between tests, LAC diagnosis is inconclusive. This testing is complicated by anticoagulation, which may yield false positive results. We investigated the impact of various anticoagulants on LAC diagnosis by evaluating the rates of dRVVT and PN discrepancy between anticoagulated and non-anticoagulated patients. Methods dRVVT and PN (LAC panel) values were examined for 1452 consecutive patients samples since April 2017, along with anticoagulant status at the time of testing. Each LAC panel was classified as positive (both dRVVT and PN abnormal), negative (both dRVVT and PN normal), or discrepant (one normal and one abnormal). The proportion of discrepant results between anticoagulated and non-anticoagulated patients was calculated and also stratified according to the class of anticoagulant. Results Discrepant results occurred in 161 of 493 anticoagulated patient samples (33%) versus 135 of 1012 non-anticoagulated patient samples (13%). The odds ratio (OR) for a discrepant result for anticoagulated patient samples was 3.15 (95% CI=2.43–4.09) compared to non-anticoagulated patient samples. When narrowed to individual anticoagulant classes, Lovenox had the lowest chance of yielding discrepant results (OR = 1.16 95% CI= 0.51–2.66), whereas Rivaroxaban (OR = 6.9 95% CI= 4.49–10.55) and Warfarin (OR = 5.4 95% CI= 3.43–8.55) had the highest odds of yielding discrepant results. Conclusions Patient anticoagulant status is an important determinant in laboratory testing for APS/LAC. The dRVVT and PN test are 3-fold more likely to yield inconclusive results when a patient is anticoagulated; the type of anticoagulant is even more critical given the large difference in rates of discrepant results for patients on Rivaroxaban and Warfarin versus patients on Lovenox. The difference in discrepancy rate is likely due to the differential impact of each class of anticoagulant on the various components of the coagulation cascade. Rivaroxaban is a direct factor X inhibitor, and Warfarin directly lowers active factor X, amongst other, levels; by contrast, Lovenox, which was not significantly discrepant, requires antithrombin to amplify inhibition of factor II and X activity.