The objectives of this study were to investigate a nuclear factor-kappa B (NFkappaB) decoy oligonucleotide (ODN) strategy on the inhibition of glioblastoma (GBM) cell line growth and to evaluate a poly(DL-lactic-co-glycolic acid) (PLGA) microparticle delivery system for the NFKB decoy ODNs in vitro. We have demonstrated that NFkappaB activation is important in regulating GBM cell line growth. Aberrant nuclear expression of NFkappaB was found in a panel of GBM cell lines, while untransformed glial cells did not display NFkappaB activity. Nuclear translocation of NFkappaB was inhibited by using a 'decoy" ODN strategy. NFkappaB decoy ODNs designed to inhibit NFkappaB resulted in a significant reduction in cell number (up to 45%) compared to control cultures after 2 days. The reduction in cell number correlated with a decrease in cyclin D1 protein expression and a commensurate decrease in Cdk-4 activity. These results provide evidence suggesting that NFkappaB mediates cell cycle progression and demonstrates a mechanism linking increased NFkappaB activity with GBM cell growth and cell cycle disregulation. Decoy ODNs were encapsulated at a yield of 66% in PLGA microparticles and released in a controlled manner in phosphate buffered saline for up to 28 days. Approximately 83% of entrapped ODNs were released by day 28. During 3 days of GBM cell line culture, the released decoy ODNs retained their biologic activity and led to significantly reduced cell number as compared to control cultures. These findings offer a potential therapeutic strategy in the control of human GBM cell line growth in vitro and suggest that PLGA microparticles may be appropriate as delivery vehicles for the "decoy" ODN strategy.