Supercritical fluid chromatography (SFC) provides a beneficial substitute for gas chromatography (GC) and liquid chromatography (LC) for certain samples because it merges the top attributes of both techniques. SFC allows the separation and analysis of compounds that GC or LC does not easily manage. These compounds are traditionally nonvolatile or thermally unstable, making GC unsuitable and lacking functional groups required for HPLC analysis.

SFC utilizes a supercritical fluid mobile phase, often CO₂, which has properties between those of a gas and a liquid. The supercritical fluid's viscosity is the same as that of gases, while the density is closer to a liquid, and the diffusion coefficient is intermediate between gas and liquid. The low critical temperature and critical pressure of CO₂ can be easily achieved and maintained.

SFC provides better analysis time and resolution than conventional HPLC. It is suitable for analyzing nonpolar organics and can also analyze polar solutes, including an organic modifier like methanol.

SFC shares similar instrumentation with GC and HPLC, with the addition of a pressure restrictor that maintains the critical pressure. Both packed and open tubular columns can be used as stationary phases in SFC. In SFC, packed columns offer a greater number of theoretical plates and can handle bigger sample volumes compared to open tubular columns. The low viscosity of supercritical media makes these columns longer than those found in LC. Open tubular columns resemble fused-silica wall-coated (FSWC) columns, while packed columns are commonly made of stainless steel. Initially, SFC utilized only polar stationary phases, but the growing use of modifiers has expanded the range of applicable phases. This makes it possible to modify retention mechanisms by adjusting the stationary and mobile phase compositions, integrating numerous HPLC stationary phases into SFC. SFC uses various detectors and allows for separating large molecules at relatively lower temperatures, resulting in increased efficiency and simplified coupling with MS or FT-IR.

Applications of SFC include the analysis of polymers, fossil fuels, waxes, drugs, and food products.