BACKGROUND: The profile of renal pathology in HIV patients is undergoing significant changes in pattern in the HAART era, with the incidence of HIV-associated nephropathy (HIVAN) decreasing and the incidence of non-HIVAN lesions increasing. CASE REPORTS: We describe 2 cases of HIV-infected patients diagnosed with diffuse infiltrative lymphocytosis syndrome (DILS) and coexistent multiple myeloma, an association that has heretofore been unreported. The cases involve a 23-year-old man and a 54-year-old man who presented with renal failure and proteinuria. Kidney biopsy in both revealed DILS and further evaluation revealed both to have multiple myeloma. CONCLUSION: DILS is a late complication of AIDS that has become extremely rare in the United States during the HAART era. However, there are patients who present without an AIDS-defining illness or cancers. The development of multiple myeloma in the setting of HIV and DILS presents a novel, heretofore unreported association that may be important to recognize in HIV/AIDS patients with kidney failure.