Sows subjected to prenatal stress have been found to produce offspring that have altered responses to stress. Our objective was to determine if exposing a sow to stress would alter the response of the offspring to lipopolysaccharide (LPS) at 2 mo of age or their response to mixing stress at 4 mo of age. Sow treatments consisted of intravenous injections of ACTH (1 IU/kg of BW), exposure to rough handling for a 10-min duration (rough), or no treatment (control) once per week from d 42 to 77 of gestation. At 2 mo of age, pigs from each treatment, 1 per litter (n = 21, 17, and 15 for the ACTH, rough, and control treatments, respectively), were challenged with 2 μg of LPS/kg of BW or saline, or served as a noninjected control. Their behavioral response to a human approach test and salivary cortisol were measured. At 4 mo of age, 1 pig from each treatment (n = 14, 14, and 15 for the ACTH, rough, and control treatments, respectively) was taken from its home pen and placed in a pen of unfamiliar pigs. At this time, a punch biopsy wound (6 × 6 mm) was created to measure the ability of the pig to heal the wound. At this same time, each pig received a 1-mL intramuscular injection of 20% ovine red blood cells (oRBC), and then a second injection of oRBC at 21 d postmixing. Blood samples were collected 3 times per week for 2 wk and then once a week for 4 more weeks. Blood samples were analyzed for cortisol, porcine corticosteroid-binding globulin, antibody response to oRBC, and nitric oxide production by macrophages. Behavior was recorded during the first 5 d after mixing. All pigs in the LPS challenge responded with characteristic sickness behavior; however, pigs in the rough treatment showed less sickness behavior than those in the other 2 treatments (P < 0.05). Maternal stress treatment did not affect (P < 0.43) salivary cortisol. Pigs from all treatments responded similarly to mixing stress with regard to cortisol, porcine corticosteroid-binding globulin, antibody titers, nitric oxide production, and hematology measures, and all pigs experienced the same amount of aggression in response to mixing. Without altering peripheral measures of stress responsivity, prenatal stress enhanced the ability of pigs to cope with a simulated immune challenge, which could prove to be an adaptation to challenging environments.