We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell–depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase–PCR (RT-PCR) of both p210^BCR-ABL and p190^BCR-ABL hybrid transcripts. Of 55 patients, 14 (including 6 T-cell–depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210^BCR-ABL positivity, increasing mixed chimerism (MC) in myeloid cells, p190^BCR-ABL positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190^BCR/ABL was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190^BCR-ABL; 10 patients tested positive for p210^BCR-ABL at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210^BCR-ABL negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190^BCR-ABL transcripts, conversion of myeloid chimerism to donor type, and, finally, p210^BCR-ABL negativity. We conclude that lineage-specific chimerism and p190^BCR-ABL messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse.