Corticosteroids are widely used as treatment for excessive scarring by intralesional injection with variable success rates. It is conceivable that systemically administered corticosteroids affect a wider range of inflammatory processes that influence wound healing and may be more successful in preventing hypertrophic scar formation. To study this presumption, we have used a standardized model of presternal scars caused by cardiothoracic surgery through a median sternotomy incision. During cardiac surgery with cardiopulmonary bypass, 1 mg/kg dexamethasone was administered preoperatively, and 0.5 mg/kg 8 hours postoperatively. The presternal scars were evaluated prospectively 2, 4, 6, 12, and 52 weeks postoperatively at standardized measuring points. The height and width of the scars were measured 12 and 52 weeks postoperatively using both a slide caliper and a 7.5-MHz ultrasound probe. Cardiopulmonary bypass was used in 31 of the 43 participants. Eleven patients (35%) in the dexamethasone group developed clinical hypertrophic scars compared with 4 patients (33%) in the control group. These differences were not statistically significant. However, cranial scars became significantly wider in the dexamethasone group compared with the control group (P = 0.04). Twelve weeks postoperatively scars were significantly higher in the dexamethasone group, both cranial (P = 0.05) and caudal (P = 0.03). The differences in scar width and height were mainly present in patients that developed hypertrophic scars. The present results suggest that administration of high-dose perioperative dexamethasone does not prevent hypertrophic scar formation. Its use together with the cardiopulmonary bypass, however, did affect scar dimensions negatively up to 52 weeks after surgery. These findings contribute to the concept of the involvement of perioperative immunologic responses in the etiology of hypertrophic scar formation.