Heterozygous mutations in Factor V Leiden (FVL) or prothrombin G20210A (PT-G20210A) are relatively common; the presence of double-heterozygosity for these mutations is rare but may be as high as 5% in patients with deep vein thrombosis (DVT). Antiphospholipid syndrome (APS) is a rare autoimmune disorder and commonly presents in adolescents and young adults. This report describes the diagnosis, treatment, and outcome for acute presentation of extensive lower extremity DVT and saddle pulmonary embolism (PE) in a previously healthy 17-year-old male found to have multiple genetic risk factors including double-heterozygosity for FVL/PT-G20210A and concurrent APS, which is rare and not well-described.