Surface damage induced on biomolecules with gas cluster ion beam (GCIB) irradiation is significantly lower than with atomic or small cluster ion beams, and for this reason, surface analysis techniques such as secondary ion mass spectrometry (SIMS) have become one of the most important applications of GCIB, particularly for microscale chemical imaging of biomolecular species. Because of the low duty-cycle in time-of-flight (TOF)-SIMS, only less than 0.1 % of the incident ion beam is used for analysis, meaning that analysis with high spatial resolution can practically be extremely lengthy. The duty cycle can be significantly improved with the orthogonal acceleration (oa) TOF method because with this method secondary ion mass spectra can be measured at high mass resolution without requiring a pulsed primary ion beam. In this study, we developed a gas cluster ion irradiation system mounted on an oa-TOF instrument and investigated the sputtering yield and secondary ion yield of arginine. Copyright © 2012 John Wiley & Sons, Ltd.