Multiple myeloma is cytogenetically heterogeneous and a hyperdiploid karyotype is considered currently to have standard risk. In this study, we investigated the clinical impact of additional-structural-chromosomal aberrations assessed by chromosome analysis in 284 patients with a hyperdiploid karyotype that were subdivided into four groups based on the complexity of additional-structural-chromosomal aberrations: group 1, no additional-structural-chromosomal aberrations (n=35); group 2, one additional-structural-chromosomal aberration (n=46); group 3, two additional-structural-chromosomal aberrations (n=39); group 4, ≥three additional-structural-chromosomal aberrations (n=164). Clinicopathological data among these groups showed no differences, except patients in group 1 had higher hemoglobin (P=0.031) and albumin (P=0.045) levels. The median follow-up was 55 months (range, 3-221). The median overall survival of patients in groups 1-4 was negatively correlated with the number of the additional-structural-chromosomal aberrations: 98, 76, 61, and 48 months, respectively (P<0.0001). In group 4, CKS1B gain, RB1, or TP53 deletions had no additional impact on overall survival; however, trisomy 3 or 15 conferred a much better overall survival, and monosomy 13 and 14 predicted a worse outcome. In addition, the overall survival of patients in groups 3 and 4 was similar to a subset of high-risk multiple myeloma cases (n=21) (P=0.387). About 192 (67.6%) patients who received stem cell transplantation did not show improved overall survival compared with non-stem cell transplantation patients (n=92; P=0.142) overall; however, they did show significantly improved overall survival in patients with refractory disease in group 4 (P=0.0084). Multivariate analysis showed that two or more additional-structural-chromosomal aberrations (P<0.0001), stages (P=0.02 and P=0.002) and relapsed disease (P=0.009) negatively impacted the overall survival. We conclude that hyperdiploid karyotypes in multiple myeloma are associated with additional-structural-chromosomal aberrations and a greater number of additional-structural-chromosomal aberrations predicts poorer clinical outcome. A hyperdiploid karyotype with ≥2 additional-structural-chromosomal aberrations at chromosomal level should be considered an independent high-risk factor.