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Background: Prior studies repeatedly showed that cultures of skin lesions diagnosed as "cellulitis" are usually negative. However, lack of a gold standard for diagnosis (against which culture might be judged) and failure to assess the human immune response are important limitations of prior work. In this pilot study, we aimed to develop a criterion standard for research on bacterial cellulitis, to evaluate the sensitivity of procalcitonin for bacterial cellulitis, and to use gene expression analysis to find other candidate diagnostic markers. Methods: We classified lesions via biopsies, 16s rRNA gene detection, culture, and histopathology. We quantified procalcitonin expression in blood. We also used Nanostring technology to quantify transcription of immunomodulators that may distinguish cases from inflamed controls. Results: Of 28 participants, 15 had a clinical diagnosis of cellulitis, six had a diagnosis of non-infectious dermatitis, and seven were normal volunteers. Of the “cellulitis” patients, three (20%) had pathogens isolated, and were designated confirmed cases. Procalcitonin was undetectable in all three. HLA-DQA1 was expressed 34-fold more in confirmed cases vs. controls (fold change of geometric mean). Heat maps depicting multiplex gene expression analysis revealed a distinct profile of gene expression in confirmed cases relative to comparators. Conclusions: Most “cellulitis” patients had microbiologically-negative biopsies. Procalcitonin was undetectable, and HLA-DQA1 elevated, in confirmed bacterial cases. Multivariable transcriptomic profiling results supported our algorithm’s ability to identify patients with true bacterial cellulitis. A larger sample may allow discovery of an immunological signature capable of distinguishing bacterial cellulitis from its mimics in clinical practice. [ABSTRACT FROM AUTHOR]