TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (E(max)) and 50% inhibitory concentrations (IC₅₀). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an E(max) of -1.43 log₁₀ copies/ml and IC₅₀ of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.