Abstract Objective To determine if the Fms‐like tyrosine kinase 3 ligand (Flt‐3L), a cytokine implicated in B cell ontogenesis and proliferation in hematologic malignancies, might be responsible for the increased numbers of circulating Bm2 and Bm2′ B cell subsets in patients with primary Sjögren's syndrome (SS). Methods Serum levels of Flt‐3L were measured in 64 patients with primary SS and in 20 healthy controls matched for age and sex. Flt‐3L and its receptor Flt‐3 were quantified in circulating B cells and in salivary gland (SG) biopsy tissues by immunofluorescence analysis. The effect of Flt‐3L on circulating B lymphocytes was then determined by coculture with cells of a human SG (HSG) epithelial cell line. Results Serum levels of Flt‐3L were increased in patients with primary SS as compared with controls (mean ± SD 135.8 ± 5.5 versus 64.4 ± 4.5 pg/ml; P < 0.001). Serum levels of Flt‐3L in primary SS patients correlated with the numbers of Bm2 and Bm2′ cells (r = 0.46, P < 0.0006), and Flt‐3 was selectively expressed in Bm2 and Bm2′ cells. B cell culture experiments showed that Flt‐3L potentiated the proliferative effect of anti‐IgM stimulation. In SGs, we found that infiltrating B cells expressed Flt‐3 and epithelial cells produced Flt‐3L. Finally, Flt‐3L levels were associated with high disease activity scores and increased risk of developing lymphoma. Conclusion Serum levels of Flt‐3L are elevated in patients with primary SS and correlate with abnormal B cell distribution. Flt‐3 is mainly expressed by Bm2 and Bm2′ cells. Serum levels of Flt‐3L might explain the clinical evolution of primary SS to B cell lymphoma that is observed in some patients, thus opening the possibility of new avenues for therapy.