The characteristics and outcome of 58 patients with acute myelogenous leukemia (AML) who experienced relapse after a first remission duration longer than 18 months (late-relapse AML) were analyzed and compared with those of 278 patients with earlier relapses. Late-relapse AML was associated with a lower incidence of antecedent hematologic disorder, leukocytosis, and elevated creatinine and lactic acid dehydrogenase (LDH) levels. A favorable karyotype (inversion of chromosome 16; translocations between chromosomes 8 and 21, or 15 and 17) was more frequent in patients whose first remission was 12 months or longer compared with less than 12 months (30% v 10%; P less than .0001). An unfavorable karyotype (chromosome 5 and 7 abnormalities, trisomy 8, other changes) was more frequent in the latter category (16% v 42%; P less than .0001). Thirty-seven of the 58 patients (64%) with late-relapse AML achieved complete remission (CR). The incidence of CR increased significantly with an increased first remission duration from less than 12, 12 to 18, and greater than 18 months (17% v 41% v 64%; P less than .0001), while the incidence of resistant disease was significantly lower (59% v 36% v 19%; P less than .0001). When effective antileukemic regimens were considered, remission rates were also significantly increased by the duration of first remission (24% v 48% v 72%; P less than .001). Compared with patients with earlier relapse, those with late-relapse AML had a longer median survival from salvage therapy (3.5 v 12 months; P less than .01), and longer median second remission durations (3.5 v 11 months; P less than .01). We conclude that late-relapse AML has unique clinical, cytogenetic, and prognostic characteristics, and remains extremely sensitive to chemotherapy with a potential cure fraction. The duration of first remission is an important prognostic parameter in AML relapse and may be useful in the design and analysis of future salvage programs.