T ransfer factor (TF) derived from donors with strong delayed hypersensitivity to coccidioidin (CDN) was administered to four patients with active disseminated or progressive pulmonary coccidioidomycosis. The clinical and immunologic response to TF was studied.Before the administration of TF, all four patients had defective thymus-derived lymphocyte (T-cell) function. In no case were lymphocytes in culture stimulated to incorporate [³H]thymidine when exposed to CDN. Cases 1 and 2 had no skin test response to CDN or other antigen, nor was antigen-induced migration inhibition factor (MIF) release detected. Cases 3 and 4 had skin reactivity to CDN as well as MIF release. Lymphocyte reactivity to phytohemagglutinin (PHA), as measured by the incorporation of [³H]thymidine, was low or absent in all.After the administration of TF, patients with negative skin tests became reactive to CDN, MIF release was present in all but case 1, and lymphocyte stimulation was present in response to CDN in all.Lymphocyte reactivity to PHA was also increased after the administration of TF in all cases. All responses to single doses of TF were transient, lasting no more than 10 days. Subsequent doses were less effective at restoring lymphocyte stimulation once it had waned. Multiple doses of TF administered at frequent intervals appear to be the most effective way to maintain lymphocyte reactivity.Clinical response to the administration of TF correlated closely with specific transfer as measured by response to CDN in skin test, lymphocyte stimulation, and MIF release. After TF administration, all patients mounted a more effective host response against the infecting fungus. In each patient, smears and cultures became negative. Fistulas, when present, diminished in extent or closed; and pulmonary infiltrates cleared. Nonspecific signs of infection such as fever, weight loss, and anorexia also improved. Clinical improvement paralleled immunologic improvement. When immunologic improvement was transient so was clinical improvement. Multiple doses of TF at frequent intervals may maintain transferred T-cell reactivity. TF may prove to be a useful adjunct in the management of patients with coccidioidomycosis. Whether TF from CDN-negative donors may have similar effects is not known and requires exploration.