Vicriviroc (VCV) is a CCR5 antagonist that blocks the viral entry of CCR5-tropic (R5) virions by binding to and inducing a conformational change in the chemokine receptor. Clinical resistance to CCR5 antagonists occurs in two phases, competitive and noncompetitive stages. In this study, we analyzed two subjects, from a phase 2b VCV clinical trial, whose quasispecies contained R5 and dual-mixed virions at the earliest recorded time of virological failure (VF). Genotypic analysis of R5-tropic patient-derived envelope genes revealed significant changes in the V1/V2 coding domain and convergence toward a more homogenous sequence under VCV therapy. Additionally, a small population of baseline clones sharing similar V1/V2 and V3 domains with the predominant VF isolate was observed. These clones were denoted preresistant based on their genotype. Preresistant clones and chimeric clones containing V1/V2 regions isolated during VF displayed high 50% inhibitory concentration (IC50) values relative to those at baseline, consistent with early competitive resistance. Genotypic analysis of the dual-tropic clones also showed significant changes in the V1/V2 region, different from the resistant R5-tropic viruses. Our findings suggest that the V1/V2 domain plays a key role in the initial step of development of drug resistance. IMPORTANCE It is believed that each CCR5 antagonist-resistant isolate will develop its own unique set of mutations, making it difficult to identify a signature mutation that can effectively predict CCR5 antagonist resistance. This may explain why we do not observe shared mutations among clinical studies. The present study examined the earliest events in the development of drug resistance with viral quasispecies that continued the use of CCR5 for entry. Genotypic and phenotypic assays demonstrated a distinct role of the variable domain V1/V2 in competitive resistance to CCR5 antagonist therapy. Thus, future studies analyzing the development of clinical resistance should focus on the relationship between the V1/V2 and V3 domains.