Background In critically ill patients, prevention of pressure ulcers is a challenge because of the high risk for multiple comorbid conditions, immobility, hemodynamic instability, and increased use of medical devices. Objectives To compare the difference in incidence rates of hospital-acquired pressure ulcers (HAPUs) in critically ill patients between those treated with usual preventive care and a 5-layered soft silicone foam dressing versus a control group receiving usual care. Secondary goals were to examine risk factors for HAPUs in critically ill patients and to explicate cost savings related to prevention of pressure ulcers. Methods A prospective, randomized controlled trial in the intensive care units at a 569-bed, level II trauma hospital. All 366 participants received standard pressure ulcer prevention; 184 were randomized to have a 5-layered soft silicone foam dressing applied to the sacrum (intervention group) and 182 to receive usual care (control group). Results The incidence rate of HAPUs was significantly less in patients treated with the foam dressing than in the control group (0.7% vs 5.9%, P = .01). Time to injury survival analysis (Cox proportional hazard models) revealed the intervention group had 88% reduced risk of HAPU development (hazard ratio, 0.12 [95% CI, 0.02-0.98], P = .048). Conclusion Use of a soft silicone foam dressing combined with preventive care yielded a statistically and clinically significant benefit in reducing the incidence rate and severity of HAPUs in intensive care patients. This novel, cost-effective method can reduce HAPU incidence in critically ill patients.