While many features are regularly considered in selecting control reagents, the responsiveness of these products to methodologic errors is frequently overlooked. To address this issue with regard to commercially prepared whole blood cell controls, mean cell volume (MCV) determinations were performed on several preserved red blood cell controls and fresh blood in the presence of various artifacts. The effects contaminating the isotonic diluent with water, saline, or bleach were compared. Although our results indicate that preserved and fresh RBCs generally behave similarly, large differences were observed in the responses to hypotonic stress among controls and between controls and fresh specimens. As this may have clinical relevance, our data highlight the need for testing the responsiveness of controls to commonly encountered methodologic variables as part of the routine evaluation of these products.