CCR5 antagonists are approved for treatment-experienced individuals, who are at risk of harboring both drug-resistant and CXCR4-utilizing (X4) HIV-1. If CXCR4 usage and drug resistance are linked, CCR5 antagonists may select for CXCR4-utilizing viruses resistant to antiretrovirals. Analysis of 117 individual viruses found that 69% of CXCR4-utilizing viruses versus 48% of R5 viruses had drug resistance mutations (P = 0.025). Linkage of X4 and drug resistance may limit the effectiveness of CCR5 antagonists.