Updated project metadata. Emerging evidence indicates that viral infection alters protein complex composition to induce both proviral and antiviral effects. However, global changes in protein complexes during infection remains understudied. Here, we employ thermal proximity coaggregation (TPCA) analysis to provide the first global and temporal characterization of changes in protein complexes during human cytomegalovirus (HCMV) infection. This dataset provides a resource to mine the alterations in protein complexes during HCMV infection. Furthermore, our subsequent experiments identified that these changes in protein complex composition and interactions functionally contribute to the progression of infection.