Retrospective analysis of 23 rheumatoid arthritis patients receiving low-dose methotrexate (MTX) demonstrated an association between the mean corpuscular volume (MCV) and hematologic toxicity. All 6 patients who developed hematologic toxicity were folate deficient, and 4 of 6 had marked macrocytosis. Furthermore, the mean MCV of the patients who developed toxicity was significantly higher than that of the controls without toxicity (P less than 0.02). This difference in MCV was associated with an increased probability of developing toxicity with time (P less than 0.005). These results suggest that sustained elevation in the MCV may be a predictor of impending hematologic toxicity due to folate depletion.