The hydrolytic degradation of four β-sultams was investigated using isothermal microcalorimetry to determine kinetic and enthalpic data. Firstly, all four compounds were analysed in the solid-state at 310 K, with a significant substituent-based stabilising/destabilising effect being observed. Secondly, the four compounds were analysed in the presence of pH 4 acetate buffer, at three temperatures (298, 310 and 323 K). Under these conditions, the substituent choice affected the rate of hydrolysis and the associated change in enthalpy for each compound. Based on the calorimetric data presented in this work, no change in reaction mechanism for the hydrolytic degradation was observed over the temperature range considered.