Abstract Tandem mass spectrometry measurements have been achieved using time‐of‐flight secondary ion mass spectrometry (TOF‐SIMS) and a post source decay (PSD)‐like method. The performance of the method has been demonstrated on model molecules with well‐known fragmentation pathways. Several lipids have been fragmented including the phosphocholine ion, phosphatidylcholines, cholesterol and vitamin E. Pure samples were analyzed, and the results compared with those obtained with the same compounds on a quadrupole‐TOF hybrid mass spectrometer. Then, the structures of some lipids which are currently observed in the TOF‐SIMS imaging of mammalian tissue sections were verified. Copyright © 2006 John Wiley & Sons, Ltd.