There exist several acquired APCR conditions such as elevated factor VIII and antibody-mediated APCR that can lead to thrombotic events such as deep venous thrombosis or pulmonary embolism. Further, several factor V Leiden-independent mutations may be associated with thrombosis. Best practice guidelines recommend testing for APCR using one of several phenotypic clot-based APCR ratio assays as an initial assay and following up positive APCR ratio results with the molecular factor V Leiden assay. Most currently available phenotypic tests are economical, with a greater than 95% concordance with molecular testing and up to 99% clinical sensitivity. Based on Medicare reimbursement rates, switching to initial-phase phenotypic testing and relying on its negative predictive value with follow-up genotypic testing on APCR-positive samples could result in a 75% reduction in costs. Although the factor V Leiden mutation assay is often ordered to determine the cause of venous thromboembolic disease, the APCR ratio assay provides greater clinical sensitivity at a lower cost. In instances when clot-based thrombosis risk testing is indicated during acute thrombosis, line-associated thrombosis, or anticoagulant therapy, the APCR is compromised and the factor V Leiden mutation assay is used as a primary assay.