The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.