Insulin-dependent diabetes mellitus (IDDM) is believed to be an autoimmune disease that results from autoimmune destruction of the insulin-secreting β-cells of the pancreas. In addition to a lymphocytic infiltration (insulitis) of the islets, patients with IDDM have autoantibodies directed against the components of the islet cells. Several β-cell proteins have been identified as candidate autoantigens. The non-obese diabetic (NOD) mouse is a murine model for spontaneous IDDM. It is generally accepted that IDDM in patients and NOD mice results from the T lymphocyte-mediated destruction of β-cells. However, the direct role of B lymphocytes in the disease process has not yet been clarified. To test directly the role of B cells in IDDM, we have generated B cell-deficient NOD mice by backcrossing the μMT−/− B cell ‘knockout mice’ onto the NOD background. The mice had no evidence of functional B cells as determined by flow cytometry and antibody production. We show that two out of seven of these mice developed insulitis and diabetes. These results suggest that despite an absence of B cells some NOD mice can still develop insulitis and diabetes.