Factors affecting the extrusion of guests from metal ion-capped decamethylcucurbit[5]uril (mc5) molecular container complexes are investigated using both collision-induced dissociation techniques and molecular mechanics simulations. For guests without polar bonds, the extrusion barrier increases with increasing guest volume. This is likely because escape of larger guests requires more displacement of the metal ion caps and, thus, more disruption of the ion-dipole interactions between the ion caps and the electronegative rim oxygens of mc5. However, guests larger than the optimum size for encapsulation displace the ion caps prior to collision-induced dissociation, resulting in less stable complexes and lower dissociation thresholds. The extrusion barriers obtained for guests with polar bonds are smaller than those obtained for similarly sized guests without polar bonds. This is likely because the partial charges on the guest allow electrostatic interactions with the ion cap and rim oxygens of mc5 during extrusion, thus stabilizing the extrusion transition state and reducing the extrusion barrier. Results from this study demonstrate simple principles to consider for designing host-guest complexes with specific guest-loss behaviors. Similar trends are observed between the experimental and computational results, demonstrating that molecular mechanics simulations can be used to approximate the relative stability of mc5 molecular container complexes and likely those of other similar complexes.