5-Fluorouracil-poly(L-lactide) (5-Fu-PLLA) microspheres have been co-precipitated in a process namely solution-enhanced dispersion by supercritical CO2 (SEDS). First, the 5-Fu is successfully micronized and then used to produce the 5-Fu-PLLA microspheres. The 5-Fu-PLLA microspheres synthesized in the SEDS process exhibited a rather spherical shape, smooth surface, and a narrow particle size distribution, where it ranged from 531 nm to 1280 nm, with a mean particle size of 793 nm. The dichloromethane residue in the 5-Fu-PLLA microspheres is 46 ppm. The average drug load of the 5-Fu-PLLA microspheres is 12.7%. The results of this study indicate that the SEDS process is an effective technique to co-precipitate 5-Fu and PLLA as composite microspheres.