Polyploidization is a common phenomenon in the evolution of flowering plants. Only a few genes controlling polyploid genome stability, fitness, and reproductive success are known. Here, we found that loss-of-function autotetraploid mutants of SMC5/6 complex subunits led to almost complete plant sterility. Hexaploid and aneuploid progeny with the extra genome copies or chromosomes were also detected. Our study suggests that the SMC5/6 complex is an important player in the maintenance of tetraploid genome stability.