We demonstrate that in response to TNF-x3b1; treatment, x3b1;B-crystallin associates with IKKx3b2; and activate its kinase activity, facilitating the degradation of phosphorylated I-kBx3b1;, a prime step in NF-x3ba;B activation. Reducing the level of x3b1;B-crystallin using the RNAi approach reduces the translocation of p65, further confirming the role of x3b1;B-crystallin in NF-x3ba;B activation. Our study shows that the ability of x3b1;B-crystallin to activate NF-x3ba;B depends on its phosphorylation status. The present study shows that x3b1;B-crystallin-dependent NF-x3ba;B activation protects myoblasts from TNF-x3b1; induced cytoxicity by enhancing the expression of the anti-apoptotic protein, Bcl 2. Thus, our study identifies yet another mechanism by which x3b1;B-crystallin exerts its anti-apoptotic activity.