The influence of the matrix effect on secondary ion yield presents a very significant challenge in quantitative secondary ion mass spectrometry (SIMS) analysis, for example, in determining the relative concentrations of metabolites that characterize normal biological activities or disease progression. Not only the sample itself but also the choice of primary ion beam may influence the extent of ionization suppression/enhancement due to the local chemical environment. In this study, an assessment of ionization matrix effects was carried out on model systems using C60 (+), Arn (+), and (H2O)n (+) cluster ion beams. The analytes are pure and binary mixtures of amino acids arginine and histidine biological standards. Ion beams of 20 keV were compared with a range of cluster sizes n = 1000-10 000. The component secondary ion yields were assessed for matrix effects using different primary ion beams and sample composition. The presence of water in the cluster beam is associated with a reduction in the observed matrix effects, suggesting that chemically reactive ion beams may provide a route to more quantitative SIMS analysis of complex biological systems.