The successful incorporation and sustained release of a hydrophilic antibiotic drug (Mefoxin, cefoxitin sodium) from electrospun poly(lactide-co-glycolide) (PLGA)-based nanofibrous scaffolds without the loss of structure and bioactivity was demonstrated. The morphology and density of the electrospun scaffold was found to be dependent on the drug concentration, which could be attributed to the effect of ionic salt on the electrospinning process. The drug release behavior from the electrospun scaffolds and its antimicrobial effects on Staphylococcus aureus cultures were also investigated. In all tested scaffolds, the maximum dosage of drug was released after 1 h of incubation in water at 37 degrees C. The usage of the amphiphilic block copolymer (PEG-b-PLA) reduced the cumulative amount of the released drug at earlier time points and prolonged the drug release rate at longer times (up to a 1-week period). The antibiotic drug released from these electrospun scaffolds was effective in their ability to inhibit Staphylococcus aureus growth (>90%). The combination of mechanical barriers based on non-woven nanofibrous biodegradable scaffolds and their capability for local delivery of antibiotics increases their desired utility in biomedical applications, particularly in the prevention of post-surgical adhesions and infections.