In a computerized case registry, containing 220 cases of sinus histiocytosis with massive lymphadenopathy (SHML), 23 patients were identified with clinical or routine laboratory findings suggestive or diagnostic of immune dysfunction. We divided the abnormalities into hematologic autoantibodies (nine patients), glomerulonephritis (three patients), Wiskott-Aldrich syndrome (two patients), joint disease (nine patients), unusual infections (three patients), and miscellaneous (six patients). Nine of the patients had more than one finding prompting inclusion in this study. In five patients, at least one abnormality preceded the onset of SHML. A major difference between this subgroup of 23 patients and the remaining registry population was the mortality rate. Ten of the 23 patients have died, and in many cases the cause of death could be linked to the immunologic abnormality. This study establishes an association between SHML and clinically significant immune dysfunction and provides further evidence that this frequently multisystemic disease may be one manifestation of disordered immunity.