Conventional cytogenetics and interphase fluorescence in-situ hybridization (FISH) identify a high-risk multiple myeloma (HRM) population characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma with FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (< 45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 (17.5%) HRM patients, induction with bortezomib and immunomodulatory agents (imid) was higher compared to non-HRM (56% vs 43%, p <0.001) with similar pre-transplant complete response (CR) (14% vs 16%, p 0.1). At day-100 post-transplant, ≥ very good partial response was 59% in HRM and 61% in non-HRM (p=0.6). More HRM patients received post-transplant therapy with bortezomib and imids (26% vs 12%, p=0.004). Three-year post-transplant progression-free (PFS) and overall survival (OS) in HRM versus non-HRM were 37% vs 49%, p <0.001 and 72% vs 85%, p <0.001 respectively. At 3-years, PFS for HRM with and without post-transplant therapy was 46(95% confidence interval 33-59)% versus 14(4-29)% and in non-HRM with and without post-transplant therapy 55(49-62)% versus 39(32-47)%; OS for HRM with and without post-transplant therapy was 81(70-90)% versus 48(30-65)% compared to 88(84-92)% and 79(73-85)% in non-HRM with and without post-transplant therapy respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (p 0.08). In addition to HRM, higher stage, <CR pre-transplant, lack of post-transplant therapy and African-American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day-100 post-transplant responses compared to non-HRM, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.