The mechanics of leukocyte [white blood cell (WBC)] deformation and adhesion to endothelial cells (EC) in shear flow has been investigated. Experimental data on transient WBC–EC adhesion were obtained from in vivo measurements. Microscopic images of WBC–EC contact during incipient WBC rolling revealed that for a given wall shear stress, the contact area increases with time as new bonds are formed at the leading edge, and then decreases with time as the trailing edge of the WBC membrane peels away from the EC. A two-dimensional model (2D) was developed consisting of an elastic ring adhered to a surface under fluid stresses. This ring represents an actin-rich WBC cortical layer and contains an incompressible fluid as the cell interior. All molecular bonds are modeled as elastic springs distributed in the WBC–EC contact region. Variations of the proportionality between wall shear stress (τw) in the vicinity of the WBC and the resulting drag force (Fs), i.e., Fs/τw, reveal its decrease with WBC deformation and increasing vessel channel height (2D). The computations also find that the peeling zone between adherent WBC and EC may account for less than 5% of the total contact interface. Computational studies describe the WBC–EC adhesion and the extent of WBC deformation during the adhesive process.