Diffuse lymphadenopathy has not been previously described in association with ankylosing spondylitis. A 22-year-old man who presented with anorexia, weight loss, shoulder pain, and diffuse lymphadenopathy is described. Lymph node biopsy showed a nonspecific pattern of reactive hyperplasia with sinus histiocytosis. Clinical evaluation disclosed active spondylitis with HLA-B27 positivity. No other cause for the lymphadenopathy was found. The association between lymphadenopathy and connective tissue diseases is discussed. Ankylosing spondylitis should be added to the differential diagnosis of patients with generalized lymphadenopathy of uncertain cause.