Many multinucleated giant cells are well-known to form from macrophage origin. Those formed from other cell types are less described, but may be as prevalent in pathological tissue. Giant multinucleated cells derived from secondary and primary fibroblast sources in various cultures with similar characteristics to foreign body giant cells are reported. Secondary-transformed NIH 3T3 fibroblasts rapidly fuse within 24 h in contact co-cultures with RAW 264.7 immortalized macrophages, while 3T3 monocultures, non-contact (transwell) co-cultures, and macrophage-conditioned media-treated 3T3 monocultures all do not fuse. Primary-derived murine fibroblasts also form multinucleated cells, both in the presence or absence of co-cultured macrophages that increase during long-term culture (5-30 days). In contrast to 3T3 fusion, this primary cell phenomenon is not due to fibroblast fusion, but rather to nuclear division without cytokinesis. That these multinucleated fibroblasts can originate via different mechanisms may influence and distinguish their behaviors in conditions under which they may arise, including various in vitro culture assays, and in certain fibroblastic pathologies such as the foreign body response, fibrosis, cancer and aged tissue.