Two structural proteins form the Papillomavirus (PV) capsids. While the functions of the major structural protein L1 are well established, the exact functions for the minor structural protein L2 are much less well defined, except for some information on a role in viral entry and maturation of infectious virions. To gain more insight in the function of L2 we used the yeast two hybrid system with the Human Papillomavirus (HPV) 11 L2 and HPV16 L2 as bait proteins to isolate putative cellular interaction partners. We identified four proteins interacting with L2 proteins of at least two different HPV types and this interaction was confirmed in vitro by pull-down assays. Further evidence for this interaction was obtained by in vivo localization studies. Two of the proteins, the previously described PATZ and a novel protein, designated PLINP, were localized in discrete nuclear domains and colocalized with L2. The third protein, designated PMSP, is a newly identified cytoplasmic protein which was recruited to nuclear dots when coexpressed with L2. The fourth protein interacting with HPV16, 11 and 1 L2, the tubular-nephritis antigen related protein (TIN-Ag-RP), shows a cytoplasmic as well as a membrane bound subcellular distribution. Taken together, our data indicate that L2 of HPVs with different phenotypes interacts with several cellular host proteins, recruits one of them to the nucleus, and is complexed with at least three cellular proteins in specific nuclear domains. These findings suggest an HPV type-independent modulatory function of L2 on host-cell functions that involves discrete nuclear domains and alteration of the subcellular distribution of cellular proteins. The interacting cellular proteins identified may play a role in the viral life cycle and establishment of viral persistence.