Chromatin structure is a key regulator of DNA transcription, replication, and repair1. In humans, the TIP60/EP400 complex (TIP60-C) is a 20-subunit assembly that impacts chromatin structure via two enzymatic activities: ATP-dependent exchange of histone H2A/H2B for H2A.Z/H2B and histone acetylation, which in yeast are carried out by two independent complexes, SWR1 and NuA4, respectively2,3. How these activities are merged in humans into one super-complex and what this association entails for their structure, mechanism and recruitment to chromatin is unknown. Here we describe the 2.4-3.3 Å resolution structure of the endogenous human TIP60-C. We find a three lobed architecture composed of SWR1-like (SWR1L) and NuA4-like (NuA4L) parts, that associate with a TRRAP activator-binding module. The huge EP400 subunit harbors the ATPase motor, traverses twice the junction between SWR1L and NuA4L, and constitutes the scaffold of the three-lobed architecture. NuA4L is completely re-arranged compared to its yeast counterpart. TRRAP is flexibly tethered to NuA4L, in stark contrast to its robust connection to the complete opposite side of yeast NuA44-7. A modeled nucleosome bound to SWR1L, supported by activity tests, suggests that some aspects of the histone exchange mechanism diverge from the yeast example8,9. Furthermore, a fixed actin module, as opposed to the mobile actin subcomplex in SWR18, the flexibility of TRRAP and the weak effect of extra-nucleosomal DNA on exchange activity, lead to a different, activator-based, mode of enlisting TIP60-C to chromatin.