Liquid matrices were developed and studied for application in the MALDI analysis of polyglycols and poly(dimethylsiloxane). Characteristic positive ion MALDI-TOF mass spectra were obtained from over 20 liquid matrices. These systems are characterized by rapid and simple preparation and exhibited good vacuum stability. The spot-to-spot and point-to-point reproducibility of signal intensity and molecular weight values are indicative of the homogeneous environment created by liquid matrices. The best performance was achieved when the chromophore, 2-cyano-5-phenyl-2,4-pentadienoic acid, was used in the analyte or analyte/mediator systems (mediator = nonabsorbing liquid) at or near saturation concentrations. Internal standards, including silver and low molecular weight polyglycols, have been successfully employed for mass calibration. Comparison of MALDI molecular weight data with those obtained from SIMS and GPC shows some systematic disparities. Possible reasons for these differences are discussed. Excellent agreement is seen between molecular weight values obtained with liquid and solid MALDI matrices. However, conventional solid MALDI matrices generally exhibit better resolution and can be applied for analysis of higher molecular weight materials. This may be related to the higher laser intensity required to produce ions from liquid matrices.