Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition characterized by infiltration of the involved organs by IgG4-bearing plasma cells. The prevalence of autoimmune diseases, associated with or occurring in patients with human immunodeficiency virus (HIV) infection, has been increasing. We describe a 58-year-old man with an undiagnosed HIV infection, which presented as chronic cervical lymphadenopathy with an elevated serum IgG4 and a very high IgE. Histologically, lymph nodes showed expanded sinusoids and burnt-out germinal centers with increased plasmacytic infiltration and collagen fiber deposition. The absolute number of IgG4+ plasma cells and the IgG4+/IgG+ plasma cell ratio was increased. The lymph nodes were enlarged and clinically the patient improved after steroid treatment. Nine months later, he was diagnosed with acquired immune deficiency syndrome, following presentation with a cavitary left lung lesion. Immunohistochemical studies on the previously resected lymph node revealed complete absence of CD4+ T-lymphocytes and increased CD8+ T-lymphocytes. The pathologic findings met the criteria of both HIV infection and IgG4-related lymphadenopathy. Our case demonstrates that further investigations for underlying HIV infection in a case of IgG4-RD are critical, especially when extremely elevated IgE is concomitantly present.