IFNA1 and B-cell chronic lymphocytic leukemia: This study demonstrates that (i) CLL cells are susceptible to both direct reovirus-induced oncolysis and reovirus-enhanced NK cell killing, (ii) reovirus activates NK cells in CLL patient samples via an IFNα- and CD14+ monocyte-dependent mechanism, and (iii) reovirus together with anti-CD20 antibodies represents a promising combination strategy for the treatment of CLL.