Indiscriminate use of antibiotics for infected chronic wounds is a global problem that may contribute to delayed healing and the development of drug-resistant micro-organisms. A prospective, descriptive cohort study of 50 male and female outpatients (mean age 52.50 [+/- 14.84] years, range 18-90) with 52 chronic wounds was conducted to investigate the microbiological profile and prevalence of drug-resistant strains in chronic nonhealing wounds to develop an evidence-based approach to antibiotic therapy until drug sensitivity reports are available. Mean wound duration was 8.23 (+/- 12.35) months (range 1.5-72), average wound size was 29.70 (+/- 37.83) cm, and most patients had a lower extremity wound and diabetes mellitus (n = 20). Pus and tissue samples were cultured and tested. Most (45) wounds contained a single organism and nine different genera were isolated. Of those, 39 were Gram-negative and 11 were Gram-positive (z = 5.50, P = <0.001). The most common organisms were Pseudomonas (21 wounds) and Escherichia coli (eight wounds). Pseudomonas aeruginosa was more common in patients with diabetes mellitus, in lower extremity ulcers, and in ulcers >20 cm2 (z-test, P <0.05). The presence of two organisms was more commonly observed in postsurgical/traumatic wounds. Ten (10) out of 55 pathogens (18.18%) isolated were drug-resistant, including Pseudomonas (seven), methicillin-resistant Staphylococcus aureus (one), and extended-spectrum beta lactamase (two--E. coli and Citrobacter). Most (70%) drug-resistant pathogens were obtained from persons with diabetes mellitus. Overall sensitivity to piperacillin and tazobactum combination was high. Because the prevalence of monomicrobial flora in chronic wounds is high, if a wound infection is suspected, empiric therapy should target the most prevalent flora. The high rate of drug-resistant Pseudomonas and MRSA strains should discourage antibiotic use in chronic ulcers before obtaining culture results.