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It is uncertain how accurately classic signs of acute infection identify infection in chronic wounds, or if the signs of infection specific to secondary wounds are better indicators of infection in these wounds. The purpose of this study was to examine the validity of the “classic” signs (i.e., pain, erythema, edema, heat, and purulence) and the signs specific to secondary wounds (i.e., serous exudate, delayed healing, discoloration of granulation tissue, friable granulation tissue, pocketing at the base of the wound, foul odor, and wound breakdown). Thirty-six chronic wounds were assessed for these signs and symptoms of infection with interobserver reliability ranging from 0.53 to 1.00. The wounds were then quantitatively cultured, and 11 (31%) were found to be infected. Increasing pain, friable granulation tissue, foul odor, and wound breakdown showed validity based on sensitivity, specificity, discriminatory power, and positive predictive values. The signs specific to secondary wounds were better indicators of chronic wound infection than the classic signs with a mean sensitivity of 0.62 and 0.38, respectively. None of the signs or symptoms was a necessary indicator of infection, but increasing pain and wound breakdown were both sufficient indicators with specificity of 100%.