Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture ‘exposed-core’ vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two ¼-length excipient-modified silicone elastomer cores – each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows – provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10–10,000 ng/g over 28 days, at least 50 and up to 50,000 times the reported in vitro IC50 value.