Sickle red cell (SS RBC) adhesion is thought to contribute to sickle cell disease (SCD) pathophysiology. SS RBC adhesion to laminin increases in response to adrenaline stimulation of β2-adrenergic receptors (β2ARs) and adenylate cyclase (ADCY6), and previous evidence suggests such activation occurs in vivo. We explored whether polymorphisms of the β2AR and ADCY6 genes (ADRB2 and ADCY6, respectively) affect RBC adhesion to laminin. We found that the β2AR arg16→gly substitution and two non-coding ADCY6 polymorphisms were associated with elevated adhesion. We postulate that ADRB2 and ADCY6 polymorphisms may influence SCD severity through the mechanism of RBC adhesion.