The diagnosis of infection in chronic wounds is challenging. Clinicians tend to rely on the classic signs and the symptoms. Quantitative tissue biopsy, the most accurate method, is rarely used because it is expensive, invasive, and difficult to perform. A recently completed clinical trial evaluating collagen/oxidized regenerated cellulose/antimicrobial matrix versus standard of care in venous leg ulcerations was reviewed. Patients with infected venous leg ulcers by clinical examination were excluded. In fact, none of the subjects in the 2 arms of the study had target ulcers that appeared to be infected at any time during the study. Quantitative biopsies of the ulcers were obtained and compared with investigator evaluation. In all, 14 of 49 subjects (28%) had bacterial counts greater than 10(5) or beta-hemolytic streptococcus despite the lack of clinical signs of infection. This analysis suggests that clinical examination is unreliable in the diagnosis of wound infection in venous leg ulcerations.