A 17-yr-old, female, captive-born reticulated giraffe (Giraffa camelopardalis) presented with acute-onset lameness of the right metacarpophalangeal (fetlock) joint. Despite multiple courses of treatment, the lameness and swelling progressively worsened over a 3.5-yr period, and the giraffe was euthanized. At necropsy, gross and microscopic changes in the right, front fetlock and associated flexor tendon sheath included villous synovial hyperplasia and the formation of discrete pigmented nodules within synovial membranes. Histologically, the nodules were composed of abundant, fibrous connective tissue with heavy macrophage infiltration, hemosiderin deposition, and distinctive, multinucleated cells that resembled osteoclasts. These findings were consistent with pigmented villonodular synovitis (PVNS), a rare condition affecting both humans and animals. Although the pathophysiology of PVNS is poorly understood, lesions exhibit features of both neoplastic and reactive inflammatory processes. This case report represents, to the authors’ knowledge, the first description of PVNS in a nondomestic ungulate.