Several autoimmune diseases (AID), including primary Sjögren's syndrome (pSS), are associated with an increased risk of lymphoma. Polymorphisms of TNFAIP3, which encodes the A20 protein that plays a key role in controlling NF-kB activation, have been associated with several AID. Somatic mutations of TNFAIP3 have been observed in the MALT lymphoma subtype frequently associated with pSS. We studied germline and somatic abnormalities of TNFAIP3 in 574 pSS patients, including 25 with lymphoma. Nineteen additional patients with pSS and lymphoma were available for exome sequence analysis. Functional abnormalities of A20 were assessed by gene reporter assays. The rs2230926 exonic variant was associated with an increased risk of pSS complicated by lymphoma (OR= 3.36 [95%CI 1.34-8.42] and OR=3.26 [95%CI 1.31-8.12], p=0.011, versus controls and pSS patients without lymphoma, respectively). Twelve of the 20 (60%) patients with paired germline and lymphoma TNFAIP3 sequence data had functional abnormalities of A20, 6 in germline DNA, 5 in lymphoma DNA and 1 in both. The frequency was even higher (77%) among pSS patients with MALT lymphoma. Some of these variants showed impaired control of NF-kB activation. These results support a key role for germline and somatic variations of A20 in the transformation between autoimmunity and lymphoma.