BACKGROUND: Healing of severe pressure injuries (PIs) in patients with multiple comorbidities requires a multifaceted and interdisciplinary approach and includes the use of support surfaces. Published clinical data guiding support surface selection are very limited. Long-term acute care hospitals frequently treat medically complex patients, many with severe PIs. PURPOSE: To compare healing rates in patients with severe PIs on air-fluidized therapy (AFT) or fluid immersion system (FIS) support surfaces. METHODS: After obtaining informed consent, patients with a stage 3 or 4 PI were randomized to receive either AFT or FIS in addition to the standard protocol of care. Baseline and weekly wound measurements were obatined using a 3-dimensional camera measurement tool. The required sample size was calculated to be 60. RESULTS: After the study had started, the long-term acute care hospital admission criteria changed, severely limiting the number of patients who met the study inclusion criteria. Only 4 patients with a stage 4 PI completed the study. Of those, 2 were on an AFT and 2 were on an FIS surface. All wounds reduced in size; 0.12 and 0.57 cm2/day for patients on AFT and 0.68 and 1.34 cm2/day for patients on FIS. All but 1 wound had a reduction in wound volume ranging from -0.2 and 0.97 cm3 to 1.78 and 4.18 cm3/day for patients on AFT and FIS, respectively. CONCLUSION: Obtaining much-needed evidence to guide support surface selections for patients with severe PIs is challenging and requires multicenter studies.