The complete genome sequence of *Methanobacterium thermoautotrophicum* ΔH, a thermophilic archaeon, has been determined using a whole-genome shotgun approach. The 1,751,377-bp genome contains 1,855 open reading frames (ORFs), with 844 (46%) assigned putative functions based on sequence similarities. Comparisons with archaeal, bacterial, and eukaryotic databases reveal that 54% of the ORF-encoded polypeptides are most similar to archaeal sequences, while 42% are more similar to bacterial sequences and 13% to eukaryotic sequences. The genome shows extensive divergence from *Methanococcus jannaschii*, with only 19% of ORFs sharing >50% identity. Gene structure and organization exhibit features typical of bacteria, including genes encoding proteins related to eukaryotic proteins. The genome contains 24 two-component sensor kinase-response regulator systems and homologs of bacterial Hsp70-response proteins DnaK and DnaJ, but lacks selenocysteine-tRNA and classically organized IS elements, prophages, or plasmids. The M. thermoautotrophicum genome is a single, circular DNA molecule with a G+C content of 49.5%, and it encodes a variety of metabolic pathways, including methanogenesis, carbon fixation, and nitrogen fixation. The genome also contains a large cluster of ribosomal protein genes and several large repeated sequences. Overall, the M. thermoautotrophicum genome provides insights into the evolution and adaptation of archaeal life forms.The complete genome sequence of *Methanobacterium thermoautotrophicum* ΔH, a thermophilic archaeon, has been determined using a whole-genome shotgun approach. The 1,751,377-bp genome contains 1,855 open reading frames (ORFs), with 844 (46%) assigned putative functions based on sequence similarities. Comparisons with archaeal, bacterial, and eukaryotic databases reveal that 54% of the ORF-encoded polypeptides are most similar to archaeal sequences, while 42% are more similar to bacterial sequences and 13% to eukaryotic sequences. The genome shows extensive divergence from *Methanococcus jannaschii*, with only 19% of ORFs sharing >50% identity. Gene structure and organization exhibit features typical of bacteria, including genes encoding proteins related to eukaryotic proteins. The genome contains 24 two-component sensor kinase-response regulator systems and homologs of bacterial Hsp70-response proteins DnaK and DnaJ, but lacks selenocysteine-tRNA and classically organized IS elements, prophages, or plasmids. The M. thermoautotrophicum genome is a single, circular DNA molecule with a G+C content of 49.5%, and it encodes a variety of metabolic pathways, including methanogenesis, carbon fixation, and nitrogen fixation. The genome also contains a large cluster of ribosomal protein genes and several large repeated sequences. Overall, the M. thermoautotrophicum genome provides insights into the evolution and adaptation of archaeal life forms.