With almost 2 million new HIV infections worldwide each year， the prevention of HIV infection is critical for stopping the pandemic. The only approved form of pre-exposure prophylaxis is a costly daily pill， and it is recognized that several options will be needed to provide protection to the various affected communities around the world. In particular， many at-risk people would benefit from a prevention method that is simple to use and does not require medical intervention or a strict daily regimen. We show that silk fibroin protein can be formulated into insertable discs that encapsulate either an antibody (IgG) or the potent HIV inhibitor 5P12-RANTES. Several formulations were studied， including silk layering， water vapor annealing and methanol treatment to stabilize the protein cargo and impact the release kinetics over weeks. In the case of IgG， high concentrations were released over a short time using methanol treatment， with more sustained results with the use of water vapor annealing and layering during device fabrication. For 5P12-RANTES， sustained release was obtained for 31 days using water vapor annealing. Further， we show that the released inhibitor 5P12-RANTES was functional both in vitro and in ex vivo colorectal tissue. This work shows that silk fibroin discs can be developed into formidable tools to prevent HIV infection.