Despite the continuing advances in treatment of open fractures and musculoskeletal wounds, infection remains a serious complication. Current treatments to prevent infection utilize surgical debridement and irrigation, and high doses of systemic antimicrobial therapy. The aim of this work was to evaluate, in vitro, the potential of a fast-resorbing calcium sulfate pellet loaded with an antibiotic. The pellet could be used as an adjunctive therapy at the time of debridement and irrigation to reduce bacterial wound contamination. Small pellets containing a binder and calcium sulfate were engineered to resorb rapidly (within 24 h) and deliver high local doses of antibiotic (amikacin, gentamicin, or vancomycin) to the wound site while minimizing systemic effects. Results from dissolution, elution, and biological activity tests against P. aeruginosa and S. aureus were used to compare the performance of antibiotic-loaded, rapidly resorbing calcium sulfate pellets to antibiotic-loaded crushed conventional calcium sulfate pellets. Antibiotic-loaded rapidly resorbing pellets dissolved in vitro in deionized water in 12-16 h and released therapeutic antibiotic levels in phosphate buffered saline that were above the minimal inhibitory concentration for P. aeruginosa and S. aureus, completely inhibiting the growth of these bacteria for the life of the pellet. Crushed conventional calcium sulfate pellets dissolved over 4-6 days, but the eluates only contained sufficient antibiotic to inhibit growth for the first 4 h. These data indicate that fast-resorbing pellets can release antibiotics rapidly and at therapeutic levels. Adjunctive therapy with fast-acting pellets is promising and warrants further in vivo studies.