Monosodium urate monohydrate (MSUM) is a potent activator of the complement system as measured by electrophoretic conversion of β,C to β, A. Activation of C3 in human serum by MSUM is both time‐ and dose‐dependent. The sensitivity of the assay allows detection of C3 activation by as little as 0.2 mg/ml of MSUM. It was observed that C3 activation is calcium dependent and eliminated by both EDTA and EGTA, a finding that demonstrated the major role of the classic pathway of complement activation. Excess calcium or magnesium alone inhibited C3 activation by MSUM in accord with the inhibitory effect of these cations on sensitized sheep cell hemolysis by complement. Heating of MSUM at 200°C for 2 hours removes the water of crystallization such that heated crystals may no longer be considered MSUM. Such treatment has a variable effect on C3 activation. Of the crystals and other material studied, only zymosan was more potent than MSUM in activating C3. Calcium pyrophosphate dihydrate and hydroxyapatite activated significant amounts of C3. Asbestos, glass wool, or a variety of microcrystalline steroids activated little or no C3.