Doxorubicin-loaded poly(butylcyanoacrylate) (PBCA) nanoparticles (NPs) were prepared by an emulsifier-free emulsion polymerization technique. The pH values of the polymerization medium and the weight ratios of doxorubicin to butylcyanoacrylate had a significant effect on the mean particle size. The particle diameter determined by transmission electron microscopy showed that the nanoparticles were predominantly less than 50 nm. Drug loading and entrapment efficiency increased with increasing pH of the medium. The surface tension of the polymerization media increased with increasing polymerization time and reached a plateau after 4 h, Doxorubicin-loaded PBCA NPs carried a positive charge, and the zeta potential of drug-loaded nanoparticles increased with the increase of the polymerization pH. Molecular weight, analyzed by gel permeation chromatography, showed that the nanoparticles mainly consisted of oligomers of PBCA. The release rate of doxorubicin from nanoparticles in biological phosphate buffer was very slow, with a half-life of 111.43 h. The results indicate that drug-loaded nanoparticles can be prepared by an emulsifier-free emulsion polymerization technique and that the resulting nanoparticles might be suitable for targeting drug delivery vehicles for clinical application.