Deep tissue injury (DTI) may develop in critically ill patients despite implementation of preventive interventions. A retrospective, descriptive study was conducted in a 620-bed, level 1 trauma, academic medical center with 7 adult intensive care units ([ICUs] cardiac surgery, trauma surgery, burn surgery, med-surgery, neurosurgery, medical, and transfer) among patients treated from January 1, 2010 to January 1, 2015. All patients 18 years of age or older that developed a sacral DTI that evolved into a Stage 3, Stage 4, or unstageable hospital-acquired pressure ulcers (HAPU) in the ICU were included. Control group data were obtained from a sample of ICU patients who did not develop a DTI during 1 random day during that time period. Data were extracted from electronic medical records to compare ICU patients that developed a DTI (n = 47; age 55 [range 28-93] years, 28 men) to those who did not develop a DTI (n = 72; age 58.9 [range 18-94] years, 46 men). Twenty-five (25) potential sociodemographic and clinical risk factors were identified from root cause analysis and measured for significance. Systolic and diastolic blood pressure, length of surgery, hematocrit levels, international ratio, dialysis treatments, history of shock or vasopressor use, and total Braden score were significantly (P <.05) different between the general and HAPU population. Braden scores were low for general ICU (15.0 ± 0.4) and HAPU patients (12.9 ± 0.3) (P = 0.03). Multivariate, univariate, and regression analysis showed patients with poor perfusion (low blood pressure) (OR 0.93; 95% CI 0.88-0.99), prolonged surgical procedures (time in surgery OR 1.20; 95% CI 1.07-1.33), or a history of dialysis (OR 4.0; 95% CI 0.060-0.99) and shock (OR 10.0; 95% CI 0.025-0.43) were at greatest risk for the development of DTI evolving into a Stage 3, Stage 4, or unstageable HAPU. For every mm Hg decrease in diastolic blood pressure, the odds of a DTI increased by approximately 7.5% (1/0.93 = 1.075). For every hour increase in surgery, the odds of developing a DTI increased by 20%. These data suggest when all modifiable (Braden Scale-identified) risk factors are addressed, as was the case in this population, patient-related risk factors may be more important for HAPU development in ICU patients than quality of nursing care variables. Future research should focus on the role of and methods to increase perfusion to prevent DTI development, especially during dialysis and surgical procedures.