The behavior of a series of alkanes bound to the molecular host cucurbituril (CB) has been systematically studied by 2D 1H NMR spectroscopy and isothermal titration calorimetry (ITC). CB and alkyltrimethylammonium (CmTA+, (CH3)3N+CmH2m+1, m=6–16) form 1:1 host–guest complexes with a high binding constant (K≈106 m−1). The shortest hexyl chain of C6TA+ can be fully encapsulated in an extended conformation inside the CB cavity, which is driven by both enthalpy and entropy. However, for the longer aliphatic chains, C8–C16, the long alkyl tails take a U-shaped conformation inside the cavity, and their complexation is dominantly or almost exclusively enthalpy-driven, owing to the increased van der Waals contact between the folded aliphatic chain and the inner wall of the host cavity. As the chain length increases from C8 to C16, the ammonium head group of the guests moves away from the portal of CB while the long aliphatic tails maintain the U-shaped conformation inside the cavity. The complexation of CmTA+ with CB follows the enthalpy–entropy compensation rule commonly observed in molecular recognition systems. For example, among the guest molecules, C12TA+ shows the highest enthalpic gain (most favorable), owing to the large van der Waals contact between the guest and the host cavity, and at the same time the most unfavorable entropic contribution, owing to the severe conformational restriction of the U-shaped alkyl chain inside the host. The enthalpy–entropy compensation plot for the complexation suggests large conformational changes of the long alkyl chains and extensive dehydration associated with the inclusion complex formation.