There are many challenges associated with adapting traditional nanoindentation methods to the study of compliant, hydrated biomaterials. These include issues related to surface detection, tip-sample adhesion, and fluid interactions. This study demonstrates that the nano-Johnson-Kendall-Roberts (JKR) force curve method can be used effectively in both air and water to overcome the challenges of surface detection and adhesion for nanoindentation of a compliant polymer. Indents were performed on poly(dimethyl siloxane) samples in air, water, and a detergent solution, with detergent used to reduce interfacial forces and provide baseline modulus measurements. The results demonstrated that errors due to adhesion dominated errors due to surface detection or fluid interactions and that JKR modeling could compensate for errors due to adhesion. Several JKR curve-fitting techniques were also evaluated, and all were found to result in moduli within 10% of the baseline moduli of the materials, demonstrating the robustness of this technique.