Poly(ADP-ribose) polymerase-1 (PARP-1, EC 2.4.2.30), a nuclear enzyme activated by DNA strand breaks, physiologically participates in DNA repair. Excessive activation of PARP-1 by cellular insults depletes its substrate β-nicotinamide adenine dinucleotide and ATP, leading to cell death. PARP-1-deficient (PARP-1^−/−) mice are protected from several forms of inflammation. In the present study, we demonstrate in PARP-1^−/− glial cells a loss of several stress-activated transcription factors as well as decreased expression of genes for cytokines and cellular adhesion molecules. We also show that augmented expression of some of these genes is independent of PARP-1 catalytic activity. These findings indicate that PARP-1 plays a pivotal role in the initial inflammatory response by modulating transcription of inflammation-linked genes.