Background: Recent molecular profiling studies from our group demonstrate that NF-κB pathway is differentially expressed in autoimmune and genetic muscle diseases (Nagaraju et al., 2005; Chen et al., 2005). The contribution of these pathways to the muscle fiber damage and dysfunction in these diseases is currently unknown. Since NF-κB represents an important and very attractive therapeutic target for drugs to treat myopathies, we decided to develop in vitro screening assay to test compounds that inhibit at NF-κB activation in C2C12 muscle cells that stably express NF-κB luciferase reporter. Methods: NF-κB reporter C2C12 stable cells were pre-treated (24h) with different concentration of compounds before inducing NF-κB activation with TNFα (10ng/ml) for next 24 h. Luciferase activity and viability was measured using a single luciferase reporter assay system (Promega) with Centro LB 960 luminometer (Berthold technologies)and by MTT assay respectively. Results: We have screened 11 potential NF-κB inhibitors. The % Inhibition and % cell viability for these compounds are as follows; Thymosin β4 (98/130), Imatinib (94/110), Pirfenidone (72/111) FGF (72/118), EGCG (94/100), Prednisone (84/152), Withaferin A (40/128), IKK inhibitor VII (92/95), IKK-2 inhibitor(92/95), Celastrol (74/101) and Bay 11-7085(32/110). We found Thymosin β4, Imatinib, EGCG, IKK inhibitor VII suppressed NF-κB activity in skeletal muscle without cytotoxocity. Conclusion: Thymosine β4, EGCG, IKKinhibitor VII and Imatinib are currently being tested for their ability to inhibit NF-κB in mouse model of autoimmune and muscle diseases. Source of research support: the Myositis Association