Abstract Introduction The immunomodulatory consequences of blood transfusion, known as transfusion‐related immune modulation (TRIM), are often not captured by hemovigilance systems. Changes to blood product manufacturing processes may impact patient outcomes. Design and Methods We conducted a retrospective study of hospitalized adults (≥18 years) in Hamilton, ON, who received ≥1 red blood cell (RBC) transfusion(s) between 2010 and 2014. Primary outcome was in hospital mortality; TRIM outcomes included respiratory failure, organ dysfunction, and sepsis. We evaluated outcomes before and after the change made by Canadian Blood Services (2012) to consolidate manufacturing of blood products in Ontario. Exclusions included autologous, washed, or deglycerolized RBC transfusions, RBCs manufactured outside select regional sites, or patients who received both pre‐/post‐consolidation RBCs. Data was obtained from the TRUST database. Logistic regression adjusted for key covariates. Results A total of 9871 pre‐ and 7871 post‐consolidation patients met inclusion criteria. Multivariate analysis demonstrated no change in in‐hospital mortality (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.89–1.14, p = 0.95), respiratory failure (OR 0.83, CI 0.65–1.06, p = 0.14) or organ dysfunction (OR 0.95, 95% CI 0.84–1.08, p = 0.42) comparing post to pre‐consolidation. However, hospital‐onset sepsis was lower post‐consolidation (OR 0.59, 95% CI 0.48–0.73, p < 0.001). Conclusions Consolidation of blood production in Ontario was not associated with changes in rates of in‐hospital mortality, respiratory failure, or organ dysfunction among transfusion recipients, but may be associated with a lower risk of sepsis. TRIM and the clinical impacts of changes to blood processing require further study.