Fluoroquinolone antimicrobials are a fluorinated, synthetic group of broad-based antibiotics that share a common mechanism of inhibiting bacterial deoxyribonucleic acid (DNA) gyrase, resulting in the replicative failure of bacterial DNA. However, their use has also been associated with tendonitis and tendon rupture due to altered collagen assembly and the sequela of decreased tensile strength. Specifically, fluoroquinolated antibiotics exert an influence on the actions of proteoglycans, which are a class of proteins instrumental in the proper assembly of collagen. This study examined the effects of the fluoroquinolated antibiotic enrofloxacin on the small, leucine-rich repeat proteoglycan decorin. Experimentation via immunoblotting, enzyme-linked immunosorbent assays, dot blotting, and immunohistochemistry revealed decreased amounts of decorin in enrofloxacin treated tendons, and decreased binding of enrofloxacin treated decorin to antibody and to collagen. These changes are most likely due to enrofloxacin induced alterations in the glycosaminoglycan attachments of decorin.