Intravenous immunoglobulin (IVIG) decreases neutrophil adhesion to endothelium and red blood cell‐neutrophil interactions in sickle cell mice undergoing vaso‐occlusion. In this Phase I clinical trial of sickle cell anemia (SCA) patients admitted with pain crisis, we evaluated the status of adhesion molecules on neutrophils in control and IVIG‐treated subjects pre‐ and post‐infusion up to 800 mg/kg, the same dose used in murine studies. Mac‐1 function significantly decreased from baseline in the low‐dose IVIG (200–400 mg/kg) cohorts. IVIG‐related adverse events may have occurred in the high‐dose (600–800 mg/kg) cohorts. There were no significant increases in neutrophil and leukocyte counts, suggesting that IVIG may more selectively inhibit Mac‐1 function as opposed to neutrophil adhesion. This study provides the first in‐human validation of pre‐clinical murine studies that IVIG can decrease Mac‐1 function. Am. J. Hematol. 90:381–385, 2015. © 2015 Wiley Periodicals, Inc.