OBJECTIVE To examine trends in Staphylococcus aureus infections in adults and children at a single academic center in 2006-2014. DESIGN Retrospective cohort study. SETTING Inpatient, outpatient, and emergency department settings in a private, tertiary referral center. PATIENTS Patients with an infection culture that grew S. aureus in January 1, 2006, through March 31, 2014. METHODS The first isolate per year for each patient was classified as community-associated (CA-), healthcare-associated (HA-), or HA-community-onset S. aureus. The incidence density of S. aureus, methicillin-susceptible S. aureus (MSSA), and methicillin-resistant S. aureus (MRSA) infections were calculated per quarter year. RESULTS Overall, 5,491 MRSA and 5,398 MSSA isolates were included. MRSA infections decreased by an average of 5.2% annually (P<.001). MRSA skin and soft-tissue infection (SSTI) incidence density decreased in adults (-3.5%; P<.001) and children (-2.9%; P=.004). MSSA infections at all anatomic sites increased by an average of 1.9% annually (P=.007) in adults and decreased 5.1% annually (P<.001) in children. MSSA SSTI incidence density increased in adults (+3.8%; P<.001) and children (+5.6%; P<.001). For MRSA and MSSA SSTI isolates, susceptibility to tetracycline and clindamycin decreased significantly. CONCLUSIONS In 2006-2014, MRSA SSTI incidence decreased among children and adults. MSSA SSTI incidence density increased in children and adults, suggesting that current empiric SSTI treatment recommendations may not be optimal. Adults experienced an overall increase in MSSA infections, which may prompt consideration of the need for horizontal infection control practices to decrease MSSA infection risk. Infect Control Hosp Epidemiol 2017;38:1226-1234.