During a 4-year national cooperative study of factor VIII inhibitors in patients with classic hemophilia, new inhibitors were identified in 31 of 1,306 patients without this finding on entry. The age of patients upon detection of an inhibitor ranged from 2-62 years with a median age of 16 years. The incidence of new inhibitors was 8 per 1000 patient-years of observation. In 29 patients baseline VIII:C was less than or equal to 0.03 units/ml; the other two patients had levels of 0.06 and 0.07 units/ml. Factor VIII:CAg was measured in entry samples of plasma from 27 subjects and generally corresponded to levels of VIII:C; the levels of VIII:CAg ranged from 0.01-0.11 units/ml in 9 cases and were less than 0.01 units/ml in the remaining 18. In no instance did an inhibitor develop without preceding exposure to infused VIII:C, appearing within 8-250 VIII:C exposure-days in all patients and within 75 exposure-days in 10 of 11 patients with maximum inhibitor values greater than 15 Bethesda units/ml. Development of an inhibitor could not be correlated with any of the following variables: bleeding tendency, intercurrent illness, drugs, and selected clinical laboratory tests including blood counts, liver enzymes, and immunoglobulins. On the basis of maximum activity and persistence of inhibitors, a spectrum of patterns could be identified. (1) In Group IA with 9 patients, inhibitors with maximum values greater than 15 Bethesda units/ml persisted throughout the remaining study period. (2) In Group IB with 2 patients with mild classic hemophilia, inhibitors with maximum values greater than 15 Bethesda units/ml disappeared despite varying continued exposure to VIII:C and PCC. (3) In Group IIA with 10 patients, inhibitors with maximum values less than or equal to 15 Bethesda units/ml persisted throughout the remaining study period. (4) In Group IIB with 3 patients, maximum values less than or equal to 15 Bethesda units/ml disappeared within 18 months despite varying continued exposure to VIII:C and PCC. (5) In Group III with 7 patients, an inhibitor with a value of less than 5 Bethesda units/ml was conclusively documented on a sing study period. (4) In Group IIB with 3 patients, maximum values less than or equal to 15 Bethesda units/ml disappeared within 18 months despite varying continued exposure to VIII:C and PCC. (5) In Group III with 7 patients, an inhibitor with a value of less than 5 Bethesda units/ml was conclusively documented on a sing study period.(ABSTRACT TRUNCATED AT 400 WORDS)