Computer analysis of a variola major virus (VAR) genomic fragment bounded by the open reading frames (ORFs) D1R and A33L, which is 47,961 bp long, revealed 46 potential ORFs. The VAR proteins were compared to the analogous proteins of vaccinia virus strain Copenhagen. The subunits of DNA-dependent RNA polymerase, as well as the transcription factors, mRNA-capping enzymes, and proteins necessary for the virion morphogenesis proved to be highly conservative within orthopoxviruses. The most pronounced differences between the VAR genome fragment under study and the corresponding vaccinia virus fragment were revealed in the vicinity of the gene encoding the A-type inclusion bodies protein. Possible functions of the analysed viral proteins are discussed.