Background: As defined by evidence-based medicine randomized controlled trials rank higher than observational studies in the hierarchy of clinical research. Accordingly, when assessing the effects of treatments on patient outcomes, there is a tendency to focus on the study method rather than also appraising the key elements of study design. A long-standing debate regarding findings of randomized controlled trials compared with those of observational studies, their strengths and limitations and questions regarding causal inference, has recently come into focus in relation to research assessing patient outcomes in transfusion medicine. Discussion: Observational studies are seen to have limitations that are largely avoided with randomized controlled trials, leading to the view that observational studies should not generally be used to inform practice. For example, observational studies examining patient outcomes associated with blood transfusion often present higher estimates of adverse outcomes than randomized controlled trials. Some have explained this difference as being a result of observational studies not properly adjusting for differences between patients transfused and those not transfused. However, one factor often overlooked, likely contributing to these variances between study methods is different exposure criteria. Another common to both study methods is exposure dose, specifically, measuring units transfused during only a part of the patient's hospital stay. Summary: When comparing the results of observational studies with randomized controlled trials assessing transfusion outcomes it is important that one consider not only the study method, but also the key elements of study design. Any study, regardless of its method, should focus on accurate measurement of the exposure and outcome variables of interest. Failure to do so may subject the study, regardless of its type, to bias and the need to interpret the results with caution.