Background: Surgical site infections (SSIs) account for 15% of all healthcare-associated infections, yet, the utility of cultures remains controversial. We hypothesized that obtaining cultures would not affect outcomes from incisional SSI.Methods: All incisional SSI from general surgery patients treated as inpatients at a single institution between 1997 and 2017 were included. Patient variables were compared by Student's t-test and Chi-square analysis. Predictors of in-hospital mortality, duration of therapy, and hospital length of stay, including the acquisition of wound cultures, were determined by multivariate (MV) logistic regression analysis.Results: In total, 2054 SSIs were identified: 1077 (52.4%) with cultures and 977 (47.6%) without. Obtaining cultures were associated with higher severity of illness/Acute Physiology and Chronic Health Evaluation (APACHE-II) score (12.4 ± 0.2 vs. 8.8 ± 0.2; P < 0.0001) and multiple comorbidities, as well as a longer antimicrobial course (13.8 ± 0.3 days vs. 9.1 ± 0.2 days; P < 0.0001), length of stay (17.4 ± 0.8 days vs. 9.7 ± 0.5 days; P < 0.0001), and mortality (8.6% vs. 4.2%; P < 0.0001). Factors independently predicting mortality included age in years (odds ratio [OR] 1.03 [95% confidence interval [CI] 1.02–1.05], P < 0.0001), APACHE-II (OR 1.17 [95% CI 1.14–1.21], P < 0.0001), days from operation to diagnosis (OR 1.01 [95% CI 1.01–1.02], P < 0.0001), and diagnosis of SSI after discharge (OR 4.98 [95% CI 2.18–11.35], P < 0.0001). Obtaining cultures (OR 1.04 [95% CI 0.65–1.64], P = 0.88) were not associated with mortality. Acquisition of cultures was independently associated with longer antimicrobial duration and length of stay.Conclusion: Routinely obtaining cultures from infected surgical incisions does not change the overall outcome and should be reserved for special circumstances, such as critical illness.