Picornaviruses are inactivated by a family of hydrophobic drugs that bind at an internal site in the viral capsid and inhibit viral uncoating. A basis for the capsid stabilization previously unrecognized is revealed by molecular dynamics simulations of the antiviral drug WIN52084s bound to a hydrophobic pocket of solvated human rhinovirus 14. Isothermal compressibilities of the complex and human rhinovirus 14 without the antiviral drug calculated from density fluctuations show that the presence of WIN52084s increases the compressibility of the viral capsid near the antiviral drug. This counterintuitive result is understandable on the basis of the empirical evidence of thermal melting temperatures and protein-folding entropies of globular proteins. Based on this evidence, we propose that a larger compressibility from drug binding confers greater thermal stability to capsid proteins by increasing the conformational entropy of capsids, thereby diminishing the entropy gain with uncoating. We suggest that compressibility is fundamental to the structural integrity of viral capsids and that examination of compressibility and antiviral activity will provide insights into the disassembly process.