Direct oral anticoagulants (DOACs) drug-to-drug interactions are underrecognized by clinicians. Apixaban has cytochrome 450 (CYP) mediated metabolism (primarily by CYP3A4). Strong inducers and inhibitors of this enzyme may cause variations in the blood level of apixaban. This report presents a patient who received a femoral artery stent and developed a large retroperitoneal hemorrhage after she was prescribed apixaban in addition to her antiretroviral therapy (AVT) regimen that included cobicistat, a strong CYP3A4 inhibitor. The patient was managed conservatively, and a repeat computed tomography scan in a subsequent admission revealed near resolution of the hematoma. The treating physicians realized that apixaban should not be prescribed with a potent CYP3A4 inhibitor like cobicistat and discontinued it.