BACKGROUND: Conflicting data exist about the impact of a monosomal karyotype (MK) on overall survival (OS) for patients with myelodysplastic syndromes (MDSs) and particularly for those with a complex karyotype (CK). This study was aimed at determining whether an MK is associated with OS independently of the number of cytogenetic abnormalities (CAs) in a population-based MDS cohort. METHODS: Cancer registry data on incident MDS cases were linked with cytogenetic data and hospital administrative data from 2000 to 2010 for the Australian state of Victoria. RESULTS: Between 2000 and 2010, 1404 incident MDS cases with cytogenetic results were identified. A CK, defined as 3 or more abnormalities, was present in 126 (9 ). A very complex karyotype (vCK), defined as 5 or more abnormalities, was present in 95 (7 ). An MK was associated with worse OS in the whole cohort (median 6 vs 39 months, P <0.001) including those with a coexisting CK (6 vs 17 months, P <0.001) or vCK (6 vs 9 months, P = 0.02). After adjustments for the number of CAs, an MK remained independently associated with OS, although its effect size decreased with increasing cytogenetic complexity (hazard ratio for an MK, 4.81; 95 confidence interval, 3.08-7.52; hazard ratio for the number of CAs, 1.22; 95 confidence interval, 1.15-1.30; and hazard ratio for the interaction between an MK and CAs, 0.83; 95 confidence interval, 0.77-0.89). CONCLUSIONS: These results support the clinical utility of an MK as an independent predictor of adverse outcomes for MDS patients, even among CK and vCK groups, although its prognostic effect decreases with increasing cytogenetic complexity. Cancer 2015;121:2892-2899.