Key Points• The monotypic and polytypic PC compartments assessed by MFC are prognostic in AL amyloidosis.• MFC may play a role in the definition of hematologic response to treatment.Multiparametric flow cytometry (MFC) in amyloid light-chain (AL) amyloidosis has not been widely adopted and, consequently, there is little information on its clinical relevance. We studied 173 patients with AL amyloidosis who underwent MFC immunophenotyping of bone marrow sample at diagnosis and 82 patients at the end of the first line of treatment (EOT). The number of monotypic plasma cells (PCs) and the polytypic PCs/bone marrow PCs (pPCs/BMPCs) ratio were analyzed. At diagnosis, ‡2.5% monotypic PCs was associated with a shorter progression-free survival (PFS) and overall survival (OS) compared with patients with <2.5% monotypic PCs (2-year PFS 41% vs 56%, P 5 .007; 2-year OS 55% vs 70%; P 5 .01). Additionally, patients with a pPCs/BMPCs ratio of £5% had a shorter PFS compared with patients with pPCs/BMPCs ratio >5% (2-year PFS 43% vs 55%; P 5 .02), but without OS difference (2-year OS 60% vs 67%; P 5 .19). In a multivariate analysis, the monotypic PCs retained an independent prediction for PFS/OS, whereas the pPCs/BMPCs ratio retained significance only for PFS. At EOT, ‡0.1% monotypic PCs was associated with a shorter PFS and OS compared with patients with <0.1% monotypic PCs (2-year PFS 31% vs 87%; P < .0001; 2-year OS 87% vs 98%, P 5 .02). In a subgroup analysis among patients who attained a very good partial response or better, the monotypic PCs at the 0.1% cutoff was predictive for progression rate but not for PFS/OS. MFC is prognostic for AL amyloidosis at diagnosis and at EOT. MFC may have a role in the definition of hematologic response. (Blood. 2017;129(1):82-87)