Several new immunodeficient mouse models for human cell engraftment have recently been introduced that include the Rag2^−/−γc^−/−, NOD/SCID, NOD/SCIDγc^−/− and NOD/SCIDβ2m^−/− strains. Transplantation of these mice with CD34⁺ human hematopoietic stem cells leads to prolonged engraftment, multilineage hematopoiesis and the capacity to generate human immune responses against a variety of antigens. However, the various mouse strains used and different methods of engrafting human cells are beginning to illustrate strain specific variations in engraftment levels, duration and longevity of mouse life span. In these proof-of-concept studies we evaluated the Balb/c-Rag1^−/−γ^−/− strain for engraftment by human fetal liver derived CD34⁺ hematopoietic cells using the same protocol found to be effective for Balb/c-Rag2^−/−γc^−/− mice. We demonstrate that these mice can be efficiently engrafted and show multilineage human hematopoiesis with human cells populating different lymphoid organs. Generation of human cells continues beyond a year and production of human immunoglobulins is noted. Infection with HIV-1 leads to chronic viremia with a resultant CD4 T cell loss. To mimic the predominant sexual viral transmission, we challenged humanized Rag1^−/−γc^−/− mice with HIV-1 via vaginal route which also resulted in chronic viremia and helper T cell loss. Thus these mice can be further exploited for studying human pathogens that infect the human hematopoietic system in an in vivo setting.