Laser-induced acoustic desorption (LIAD) of neutral molecules coupled with electron and chemical ionization was examined as an analysis method for nonvolatile organic and biomolecules in Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry. LIAD involved the production of a high amplitude acoustic wave by laser ablation of a copper or titanium foil from the opposite side of where the sample was deposited. The experiment was carried out with a simple probe designed for transmission mode laser desorption. Large amounts of neutral molecules were desorbed this way, but ions were not detected. The desorbed neutral molecules were ionized by 70 eV electron ionization or by reactions with reagent ions that were generated, isolated, and trapped in the ICR cell. Strong, reproducible signals were obtained in these experiments. The applicability of the method was demonstrated for a wide variety of molecules, including an organic salt, steroids, sugars, oligopeptides, nucleic acid bases, nucleosides, and synthetic polymers. For example, the tetrapeptide val-ala-ala-phe was volatilized by LIAD and ionized by a proton transfer reaction. The ions were stored in the FT-ICR cell for up to 30 s before detection. The base peak in the spectrum obtained corresponds to the protonated peptide, which indicates that the neutral peptide was desorbed intact. In contrast, thermal desorption of this peptide leads to substantial degradation. Based on this and other results obtained, LIAD combined with postdesorption ionization in an FT-ICR shows promise as a practical method for the analysis of thermally labile, nonvolatile molecules. A special advantage of this approach is that it allows better control of the ionization step (through selection of reagent ions) and a broader choice of ionization modes (e.g. group transfer, addition/elimination) than laser desorption/ionization methods, such as matrix-assisted laser desorption/ionization (MALDI).