The rational regulation of the pK(a) of an ionizable group in a synthetic device could be achieved by controlling the entropy of the linker connecting the hydrogen bond forming domains. We demonstrate this by designing a set of pH-responsive synthetic DNA-based nanoswitches that share the same hydrogen bond forming domains but differ in the length of the linker. The observed acidic constant (pK(a)) of these pH-dependent nanoswitches is linearly dependent on the entropic cost associated with loop formation and is gradually shifted to more basic pH values when the length of the linker domain is reduced. Through mathematical modeling and thermodynamic characterization we demonstrate that the modulation of the observed pK(a) is due to a purely entropic contribution. This approach represents a very versatile strategy to rationally modulate the pK(a) of synthetic devices in a highly predictable and accurate way.