We analyzed effects of successive changes in prevention and treatment of chronic GVHD in 405 patients with aplastic anemia and refractory anemia given IIIA-matched hematopoietic stem cell transplantation (HSCT) from. 1970-1997. For analysis, patients were divided into group 1, transplantations from 1970-1976; group H, 1977-1983; group M, 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 H and M. 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 H; 80%, 10%, and 10% in group M; 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 H 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.