The performance characteristics of the particle beam interface (PB) coupled to supercritical fluid chromatography (SFC) and mass spectrometry (MS) were assessed with pure and methanol-modified CO₂. Factors which affect the nebulization and the subsequent desolvation of the droplets were assessed. The quantitative performance was evaluated yielding a limit of detection (LOD) of 40 ng (caffeine) for scan data which is some 3 to 25 times lower than previously reported studies. Operation of the SFC-PB-MS system was found to be highly dependent on the mobile phase characteristics (flow rate and composition). Between 0.1 to 0.64 mL/min liquid CO₂ flow, relatively stable operation of the system was determined; whereas beyond this range significant losses in sensitivity were observed. Mobile phase composition was shown to have a dramatic effect with 4% methanol-modified CO₂ yielding the most sensitive results; whereas, no detection was possible with pure CO₂. This lack of sensitivity with pure CO₂ and dependence of sensitivity on mobile phase composition, presented a problem in method development. The SFC-PB-MS system was therefore modified by employing a particle forming solvent (PFS). The purpose of the PFS was to aid in the formation of an aerosol. With the PFS solvent, mobile phase composition had no effect on sensitivity and detection of analytes eluted with pure CO₂ was achieved. The nature, composition, and flow rate of the PFS were found to be crucial to the optimum operation. Quantitative performance of the system was improved by a factor of 4 to 5 over the prior system. The analysis of pesticides, steroids, and polyaromatic hydrocarbons was achieved with the SFC-PB-MS system. The resulting EI spectra were artifact-free and gave good matches on comparing with on-line library spectra. Packed column SFC, however, is only able to handle directly non-polar to medium polar analytes. Thus for polar to highly polar analytes (peptides, proteins) liquid introduction (infusion, flow injection, chromatography) is the preferred method of sample delivery to the MS. Furthermore because of the polar nature and thermal lability of these compounds conventional ionization methods (EI, CI) are not suitable. Factors which have ramification on sample handling (flow rate, solution composition) were studied. The high sample flow rate capability was dependent on effective nebulization and desolvation. Thus, needle distance/angle and bath gas flow setting played a critical role in the performance of the ES-MS. The utility of the system was demonstrated by analysis of gramicidin s, myoglobin, and tryptic peptides of cytochrome c. / Ph. D.