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Objectives: Despite advances in surgical techniques and management, surgical site infection (SSI) is still important after cardiovascular surgery. We investigated to determine whether or not preoperative nasopharyngeal cultures (NCx) can predict SSI and its microbial spectrum. Methods: A retrospective review was done in 1226 consecutive patients undergoing NCx and cardiac and thoracic aortic surgery via median sternotomy who were cared for with the standard SSI bundle between 2013 and 2018. Microorganisms isolated from the NCx and SSI pathogens were counted to explore the microbial pattern and associated variables in patients with and without postoperative SSI. Perioperative management was not changed by collection of preoperative NCx. Results: There were 1281 and 127 microorganisms, including coagulase-negative Staphylococcus as the most prevalent, isolated from 784 nasal and 111 pharyngeal specimens, respectively. Postoperative SSI occurred in 31 patients (2.47%), including chest, groin, and leg SSI. Significant coincidence of the SSI pathogens with the NCx microorganisms was not observed. However, the patients with SSI showed significantly higher positive rates of preoperative NCx than those without SSI. The sensitivity/specificity of NCx for SSI were 81%/37% for nasal and 45%/92% for pharyngeal, respectively. The negative predictive value of NCx for ruling out SSI was 98.6% for nasal and 98.4% for pharyngeal, respectively. Independent risk factors for postoperative SSI included female sex, diabetes mellitus, positive preoperative NCx, and postoperative use of Portex Mini-Trach (Smiths Medical, Minneapolis, Minn) or tracheostomy on multivariate analysis. Conclusions: Preoperative NCx may be useful to predict SSI after open heart surgery via median sternotomy, as well as screening for methicillin-resistant Staphylococcus aureus.