As human phosphodiesterase (PDE) proteins are attractive drug targets, a large number of selective PDE inhibitors have been developed. However, since the catalytic sites of PDE isoforms are conserved in sequence and structure, it remains unclear how these inhibitors discriminate PDE isoforms in a selective manner. Here we perform long-time scale molecular dynamics (MD) simulations to investigate the spontaneous association processes of a highly selective PDE2A inhibitor (BAY60-7550) with the catalytic pockets of six PDE isoforms. We found that the free-energy landscapes of PDE:BAY60-7550 interactions on the PDE surfaces are very different between various PDE isoforms; and the free-energy landscape of PDE2A forms a favorable low-energy pathway that not only drives BAY60-7550 toward the target binding site, but also guides BAY60-7750 to adopt its native binding conformation known from crystal structure. Thus, this study reveals that the inhibitor interactions with the PDE surface residues play an important role in its high selectivity for PDE2A, and thereby provides new fundamental insights into the PDE isoform-specific inhibitor selectivity.