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Background. Livestock-associated Staphylococcus aureus (LA-SA) has been documented worldwide. However, much remains unknown about LA-SA colonization and infection, especially in rural environments.Methods. We conducted a large-scale prospective study of 1342 Iowans, including individuals with livestock contact and a community-based comparison group. Nasal and throat swabs were collected to determine colonization at enrollment, and skin infection swabs over 17 months were assessed for S. aureus. Outcomes included carriage of S. aureus, methicillin-resistant S. aureus (MRSA), tetracycline-resistant S. aureus (TRSA), multidrug-resistant S. aureus (MDRSA), and LA-SA.Results. Of 1342 participants, 351 (26.2%; 95% confidence interval [CI], 23.8%–28.6%) carried S. aureus. MRSA was isolated from 34 (2.5%; 95% CI, 1.8%–3.5%) and LA-SA from 131 (9.8%; 95% CI, 8.3%–11.5%) of the 1342 participants. Individuals with current swine exposure were significantly more likely to carry S. aureus (prevalence ratio [PR], 1.8; 95% CI, 1.4–2.2), TRSA (PR, 8.4; 95% CI, 5.6–12.6), MDRSA (PR, 6.1; 95% CI, 3.8–10.0), and LA-SA (PR, 5.8; 95% CI, 3.9–8.4) than those lacking exposure. Skin infections (n = 103) were reported from 67 individuals, yielding an incidence rate of 6.6 (95% CI, 4.9–8.9) per 1000 person-months.Conclusions. Current swine workers are 6 times more likely to carry MDRSA than those without current swine exposure. We observed active infections caused by LA-SA. This finding suggests that individuals with livestock contact may have a high prevalence of exposure to, and potentially infection with, antibiotic-resistant S. aureus strains, including LA-SA strains.