A series of 2-(p-substituted-benzyl)-5-[[4-(p-chloro/fluoro-phenyl)piperazin-1-yl]ace tamido]-benzoxazoles were synthesized in need of new compounds for the fight against microbial pathogens. Their structures were elucidated by spectral techniques. These new derivatives, along with previously synthesized 2-(p-substituted-benzyl)-5-substituted-benzoxazoles, were evaluated for their antibacterial and antifungal activities against standard strains and drugresistant isolates in comparison with ampicillin, gentamicin sulfate, ofloxacin, vancomycin, fluconazole, and amphotericin B trihydrate. The minimum inhibitory concentration (MIC) of each compound was determined by a two-fold serial dilution technique. The compounds were found to possess a broad spectrum of antimicrobial activities with MIC values of 32-256 μg/ml. Although standard drugs were more active against the pathogenes employed in this study, the activities of the new benzoxazoles and reference drugs against drug-resistant isolates of the microorganisms were largely similar. © 2012 Verlag der Zeitschrift für Naturforschung, Tübingen.