An isothermal titration microcalorimeter having a volume of 4 ml and capable of temperature control to ± 2 × 10−5°C is described. Major components include a constant temperature water bath controlled to ± 3 × 10−4°C, a platinum reaction vessel, and an isothermal control circuit consisting of constant Peltier thermoelectric cooling and variable Joule heating controlled by a thermistor in an ac Wheatstone bridge circuit. The calorimeter was tested by measuring the heat of ionization of water and was found to produce data accurate to ±0.1% for this system. The instrument is ideally suited for measuring heats where small samples are used such as in the investigation of many biological systems.