Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported. We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC. There was a very high prevalence of promoter mutations, comparable with that of ATC, and these co-occurred with and mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes - and - were identified. There was a high frequency of mutations in and these were mutually exclusive to promoter mutations and also to and mutations. In addition, a high frequency of mutations in was identified and these co-occurred with mutations and mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in pathway effectors, subunits, and histone methyltransferases. These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of promoter mutations, mutations, mutations, and chromosome 1q gain highlight their likely association with tumor virulence. .