Objectives: To present a unique case where detection of oligoclonal bands in serum led to the diagnosis of human immunodeficiency virus (HIV) infection. Methods: A 64-year-old man treated for hypertension for 11 years had laboratory tests ordered by his primary care physician, including serum protein electrophoresis (SPE) and serum immunofixation electrophoresis. Results: The total protein serum protein concentration was elevated at 9.6 g/dL. The SPE showed an oligoclonal pattern of multiple discrete bands in the γ region; the concentration of one band was approximately 1 g/dL and that of two bands was approximately 0.5 g/dL each, with multiple smaller overlapping bands at approximately 0.1 g/dL each. All fractions by SPE were within reference intervals except for the γ fraction, which was elevated at 3.4 g/dL. The IFE demonstrated that this oligoclonal pattern was a mixture of multiple bands of immunoglobulin G (IgG)–λ and IgG-κ. The patient’s HIV-1 antibody screen and HIV-1 Western blot were positive on three subsequent visits with strongly positive HIV-1 antibody index values of more than 50 (cutoff value of 1.0 for reactivity). Conclusions: The etiology of HIV-associated clonal immunoglobulin bands is hypothesized to result from chronic antigenic stimulation leading to B-cell hyperplasia. In this regard, hypergammaglobulinemia is a well-known consequence of HIV infection due to B-cell activation, associated with paraproteins, and can be seen at any stage of the disease.