Full mass spectra of high resolving power are obtained from 0.2 nL sample volumes of large (> 10 kDa) nucleotides and proteins using a new electrospray ionization (ESI) system combined with Fourier transform mass spectrometry. The ESI needles are fabricated by laser-heated pulling of fused-silica tubing (5-20 microns i.d.), followed by chemical etching and surface metalization. Total analyte loaded at the instrument of 8.6 fmol and 216 amol produces signal-to-noise ratios of 400:1 and 60:1, respectively, and resolving power of > 10(5) for full mass spectra, while the total amount of material consumed is approximately 150 and 10 amol, respectively.