Risk stratification is critical in the care of patients with myelodysplastic syndromes (MDS). Approximately 10% have a complex karyotype (CK), defined as more than two cytogenetic abnormalities, which is a highly adverse prognostic marker. However, CK-MDS can carry a wide range of chromosomal abnormalities and somatic mutations. To refine risk stratification of CK-MDS patients, we examined data from 359 CK-MDS patients shared by the International Working Group for MDS. Mutations were underrepresented with the exception of
TP53
mutations, identified in 55% of patients.
TP53
mutated patients had even fewer co-mutated genes but were enriched for the del(5q) chromosomal abnormality (
p
< 0.005), monosomal karyotype (
p
< 0.001), and high complexity, defined as more than 4 cytogenetic abnormalities (
p
< 0.001). Monosomal karyotype, high complexity, and
TP53
mutation were individually associated with shorter overall survival, but monosomal status was not significant in a multivariable model. Multivariable survival modeling identified severe anemia (hemoglobin < 8.0 g/dL
), NRAS
mutation,
SF3B1
mutation,
TP53
mutation, elevated blast percentage (>10%), abnormal 3q, abnormal 9, and monosomy 7 as having the greatest survival risk. The poor risk associated with CK-MDS is driven by its association with prognostically adverse
TP53
mutations and can be refined by considering clinical and karyotype features.