Purpose: To quantify the effect of silicone hydrogel crosslink density on the adhesion at corneal epithelial cells/silicone hydrogel contact lens interface. Methods: A custom-built rheometer, referred to as the live cell monolayer rheometer, was used to measure the adhesive strengths between corneal epithelial cell monolay-ers and silicone hydrogel lens surfaces. The resulting stress relaxations of senofilcon A– derived silicone hydrogel materials with varying crosslinking densities and delefilcon A were tested. Senofilcon A–like materials labeled L1, L2, L3, L4, and L5 contained crosslinker concentrations of 1.2, 1.35, 1.5, 1.65, and 1.8 wt%, respectively. The residual modulus measured from the live cell monolayer rheometer provided a direct indication of adhesive attachment. Results: Within the senofilcon-derived series, the adhesive strength shows a surpris-ing minimum with respect to crosslink density. Specifically, L1 (1.20%) has the highest adhesive strength of 39.5 ± 11.2 Pa. The adhesive strength diminishes to a minimum of 11.2 ± 2.1 Pa for L3, whereafter it increases to 14.5 ± 2.5 Pa and 18.1 ± 5.1 Pa for L4 and L5, respectively. The delefilcon A lens exhibits a comparable adhesive strength of 27.8 ± 6.3 Pa to L1. Conclusions: These results demonstrated that increasing the crosslink density has a nonmonotonic influence on the adherence of lenses to mucin-expressing corneal epithelial cells, which suggests a competition mechanism at the cell/lens interface. Translational Relevance: Because the adhesiveness of contact lenses to ocular tissues may impact the comfort level for lens wearers and affect ease of removal, this study suggests that lens adhesion can be optimized through the control of crosslink density.