Human cytomegalovirus (HCMV) establishes a persistent life-long infection, which is usually asymptomatic, but poses life-threatening risks in immunocompromised patients. HCMV establishes latency in CD34+ haematopoietic progenitor cells, with reactivation occurring upon terminal differentiation to myeloid dendritic cells (DCs) and macrophages. In DCs, IL-6 triggers reactivation via the concomitant activation of ERK-MAPK and Src family kinases (SFKs) which promote chromatin remodelling of repressed MIEP (Major Immediate Early Promoter) to an active form. SFK activity has been shown to promote MOZ histone acetyltransferase recruitment to the MIEP. However, SFKs do not bind DNA directly leading us to investigate the mechanism that translates SFK activity into MOZ recruitment to the MIEP. A phosphor-proteomic screen performed in reactivating DCs suggested the STAT5B paralog of the STAT5 family as a candidate. Here we show that STAT5 binds to the MIEP in DCs upon IL6 activation and that the transfected MIEP is responsive to STAT5 over-expression and is enhanced by IL-6 and can be reversed when co-incubated with a gp130 inhibitory peptide. Consistent with these transfection studies, pharmacological and genetic approaches reveal that IL-6 induced viral reactivation in DCs is STAT5-dependent but intriguingly was observed to be independent of upstream JAK activation. Intriguingly, HCMV reactivation in PMA stimulated macrophages was observed to be JAK-dependent but STAT5 independent. Taken together, these data reinforce that mechanisms driving HCMV reactivation are ligand and cell-type specific and suggest an intriguing role for JAK-independent STAT5 activity in HCMV reactivation in response to IL-6 which we hypothesise is via SFK activation.