Chronic wounds associated with vascular disease, diabetes mellitus, or aging are leading causes of morbidity in western countries and represent an unresolved clinical problem. The development of innovative strategies to promote tissue repair is therefore an important task that requires a more thorough analysis of the underlying molecular pathophysiology. We propose that the understanding of the complex biological events that control tissue repair or its failure largely benefits from a broad analytical approach as provided by novel proteomic methodologies. Here we present the first comparative proteome analysis of wound exudates obtained from normal healing or nonhealing (venous leg ulcer) human skin wounds. A total of 149 proteins were identified with high confidence. A minority of proteins was exclusively present in exudate of the healing wound (23 proteins) or the nonhealing wound (26 proteins). Of particular interest was the differential distribution of specific proteins among the two different healing phenotypes. Whereas in the exudate obtained from the healing wound mediators characteristic for tissue formation were abundantly present, in the exudate obtained from the nonhealing wound numerous mediators characteristic for a persistent inflammatory and tissue destructive response were identified. Furthermore, the study also revealed interesting results regarding the identification of new proteins with yet unknown functions in skin repair. This analysis therefore represents an important basis for the search for potential biomarkers, which give rise to a better understanding and monitoring of disease progression in chronic wounds.