The impact of drug-drug interactions (DDIs) between interferon-free direct acting antiviral (DAA) regimens and antiretrovirals (ART) among HIV/HCV co-infected individuals in clinical practice settings is unknown. A single-center, retrospective chart review of co-infected patients was conducted from June 2014 to February 2015. Significant interactions between simeprevir (SMV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (3D regimen) with ART were identified based on available literature. SMV had the largest number of DDIs and was further investigated to determine the feasibility of ART switch to allow for DAA use. Of 127 subjects, 23% had advanced liver disease; 86% of those with known HCV genotype were HCV genotype 1. An ART switch allowing use of SMV, LDV, and 3D regimen was recommended in 97/127 (76%), 81/127 (64%), and 91/127 (72%) patients, respectively. Subjects on PI/r regimens had limited options for ART switch, with 40% of these patients unable to be switched to an ART regimen that avoided the use of a PI. In conclusion, the majority of HIV/HCV co-infected patients will be recommended to switch ART prior to use of interferon-free, DAA regimens, and an ART switch may not be feasible for more than a third of patients on a boosted PI. DDIs between ART and DAAs represent an additional barrier to treatment efficacy in clinical practice settings that are unaccounted for in clinical trials.