The in vivo pathogenicity, transmissibility, and fitness of the SARS-CoV-2 Omicron (B.1.1.529) variant are unclear. We compared these virological attributes of this new variant of concern with those of the Delta (B.1.617.2) variant in a Syrian hamster model of COVID-19. Omicron-infected hamsters lost significantly less body weight and exhibited reduced clinical scores, respiratory tract viral burdens, cytokine/chemokine dysregulation, and lung damage than Delta-infected hamsters. Both variants were highly transmissible via contact transmission. In non-contact transmission studies, Omicron demonstrated similar or higher transmissibility than Delta. Delta outcompeted Omicron without selection pressure. This scenario drastically changed once immune selection pressure with neutralizing antibodies active against Delta but poorly active against Omicron was introduced. Next-generation vaccines and antivirals effective against this new VOC are urgently needed.