We analyzed effects of successive changes in prevention and treatment of chronic GVHD in 405 patients with aplastic anemia and refractory anemia given HLA-matched hematopoietic stem cell transplantation (HSCT) from 1970-1997. For analysis, patients were divided into group I, transplantations from 1970-1976; group II, 1977-1983; group III, 1984-1990; and group IV, 1991-1997. The overall incidence of chronic GVHD was 28%. Incidences of chronic GVHD for groups I through IV were 20%, 46%, 41%, and 22%, respectively, reflecting added buffy coat infusions in groups II and III. Five-year survival rates of patients with chronic GVHD for groups I through IV were 58%, 74%, 82%, and 76%, respectively (NS). Among group I patients, 50% were alive off immunosuppression, none were alive on immunosuppression, and 50% died. These figures were 76%, 0%, and 24% in group II; 80%, 10%, and 10% in group III; and 64%, 21%, and 14% in group IV patients. More serious infections and skin contractures were seen in group I than in groups II, III, and IV (P = .0001, .02, .01 and P =.0003, .001, .05, respectively). Lung complications, aseptic necroses, depression, and Karnofsky scores were comparable among groups. Gastrointestinal complications seemed less frequent among groups II through IV. Diabetes mellitus was more frequent in group IV than in groups I through III (P = .008). Secondary malignancies occurred in 33%, 6%, 3%, and 0% of patients in the 4 groups, respectively. In conclusion, over 28 years, chronic GVHD has remained challenging, with only slight improvements in quality of life. Decisive improvements in therapy and survival will have to await both a better understanding of the immunological events underlying chronic GVHD and better infection prevention and control.