We report for the first time on significant molecular secondary ion yield increases by modifying the chemistry of a water cluster primary ion beam. This was demonstrated using 70 keV ion beams of 0.15 eV/amu. For the neutral drug Bezafibrate, secondary ion yield enhancements ×5-10 were observed when replacing the Ar carrier gas in a water gas cluster ion beam (GCIB) source with a mixture containing 12% CO2 and 2% O2 in Ar. For the cationic drug Ranitidine the ion yield enhancements using the CO2-containing carrier gas were up to ×20-50 in positive mode and ×2-4 in negative mode. The extent of molecular fragmentation was very similar from both cluster beams. We conclude that additional chemically reactive species are present in the impact zone using the (H2O/CO2)n projectile which promote the formation of secondary ions of both polarity through projectile impact-induced chemical reactions. This methodology can be applied to further extend the capabilities of high-resolution 3-dimensional mass spectral imaging using reactive GCIB-SIMS.