Subcutaneous mineral oil injection is an old-fashioned practice used mostly for cosmetic purposes. Infection, ulceration, subcutaneous nodules, and autoimmune activation are among the known adverse effects. Immunodeficiency has not been previously reported in association with mineral oil injection. To report the case of a 43-year-old woman who performed long-term self-administration of mineral oil and was found to have both cellular immunodeficiency and autoimmunity. We performed an immunological evaluation. Throat, induced sputum, urine, and blood cultures were examined for microorganisms. Pelvic computed tomography, inguinal lymph node biopsy, bone marrow biopsy, and liver biopsy were also performed. Laboratory results revealed peripheral lymphopenia, very low absolute numbers of lymphocyte subpopulations, and a markedly impaired lymphocyte proliferative response to mitogens (phytohemagglutinin and concanavalin A) and recall antigens (mumps, Candida albicans, purified protein derivative, and tetanus toxoid). The cultures were negative for microorganisms. The pelvic computed tomogram demonstrated areas of diffuse oil-density signals throughout the subcutaneous tissue in the gluteal area and proximal lower extremities, as well as bilateral inguinal lymphadenopathy. A lymph node biopsy specimen showed lipid granulomas and necrotizing lymphadenitis. A bone marrow biopsy specimen demonstrated hypercellular marrow with normal trilineage hematopoesis. Increased serum transaminase levels, hypoalbuminemia, positive anti-extractable nuclear antigen and anti-Ro antibodies, and plasma cells in the liver suggested an autoimmune process. Mineral oil administration may be associated with both cellular immunodeficiency and autoimmunity. Patients who have received long-term administration of a foreign substance should undergo a comprehensive immunological evaluation.