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Background: The CARMA-BCL10-MALT1 complex recruits signaling components leading to activation of NF-κB transcription factor. Results: The Rho guanine nucleotide exchange factor Net1 binds to BCL10, CARMA1, and CARMA3. Conclusion: Net1 modulates activation of NF-κB transcription factor. Significance: The results shown are important to understand events that control NF-κB activation and the mechanisms by which Net1 promotes cellular transformation., The molecular complexes containing CARMA proteins have been recently identified as a key components in the signal transduction pathways that regulate activation of nuclear factor κB (NF-κB) transcription factor. Here, we used immunoprecipitation coupled with mass spectrometry to identify cellular binding partners of CARMA proteins. Our data indicate that the Rho guanine nucleotide exchange factor Net1 binds to CARMA1 and CARMA3 in resting and activated cells. Net1 expression induces NF-κB activation and cooperates with BCL10 and CARMA proteins in inducing NF-κB activity. Conversely, shRNA-mediated abrogation of Net1 results in impaired NF-κB activation following stimuli that require correct CARMA-BCL10-MALT1 complex formation and functioning. Microarray expression data are consistent with a positive role for Net1 on NF-κB activation. Thus, this study identifies Net1 as a CARMA-interacting molecule and brings important information on the molecular mechanisms that control NF-κB transcriptional activity.