Background: In instances of suspected cutaneous infection, the standard of care includes obtaining skin biopsy specimens for histology and tissue culture. Few studies have compared the clinical utility of each test.Objective: To assess the concordance of results between tissue culture and histology, as well as the clinicopathologic features that may influence the diagnostic yield of each test. Methods: A retrospective review of all patients who underwent skin biopsy for histology and tissue culture at New York University from 2013 through 2018.Results: Of 179 patients, 10% had positive concordance, 21% had positive tissue culture only, and 7% had positive histology only. We calculated a kappa correlation coefficient of 0.25 between histology and tissue culture (reference, 0.21-0.39 indicates minimal agreement). Histology exhibited higher sensitivity in detecting fungi, whereas tissue culture was more sensitive in identifying Gram-negative bacteria. Antimicrobial use before biopsy led to significantly fewer positive cultures (37.5% vs 71%; P = .023) in patients ultimately diagnosed with infection.Limitations: This study was conducted at a single institution, thereby restricting its broad applicability. The lack of a validated criterion standard to diagnose infection also limits interpretation of the results.Conclusion: Tissue culture and histopathology often yield discordant results. Dermatologists should recognize specific limitations, yet high clinical utility in special circumstances, of tests when approaching cases of suspected infection.