Human cytomegalovirus (HCMV) is beta herpesvirus that persists indefinitely in the human host through a protracted, latent infection. The polycistronic UL133-UL138 gene locus of HCMV encodes genes regulating latency and reactivation. While UL138 is pro-latency, restricting virus replication in CD34+ hematopoietic progenitor cells (HPCs), UL135 overcomes this restriction for reactivation. By contrast, UL136 is expressed with later kinetics and encodes multiple protein isoforms with differential roles in latency and reactivation. Like UL135, the largest UL136 isoform, UL136p33, is required for reactivation from latency in hematopoietic cells. Furthermore, UL136p33 is unstable, and its instability is important for the establishment of latency and sufficient accumulation of UL136p33 is a checkpoint for reactivation. We hypothesized that stabilizing UL136p33 might overcome the requirement of UL135 for reactivation. To test this, we generated recombinant viruses lacking UL135 that expressed a stabilized variant of UL136p33. Stabilizing UL136p33 did not impact replication of the UL135-mutant virus in fibroblasts. However, in the context of infection in hematopoietic cells, stabilization of UL136p33 strikingly compensated for the loss of UL135, resulting in increased replication in CD34+ HPCs and in humanized NOD-scid IL2Rgammacnull (NSG) mice. This finding suggests that while UL135 is essential for reactivation, it functions at steps preceding the accumulation of UL136p33 and that stabilized expression of UL136p33 largely overcomes the requirement for UL135 in reactivation. Taken together, our genetic evidence indicates an epistatic relationship between UL136p33 and UL135 whereby UL135 may initiate events early in reactivation that will result in the accumulation of UL136p33 to a threshold required for productive reactivation.