Severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood lymphocytes (hu-PBL) were evaluated as an animal model for demonstrating dengue (DEN) viral infection. Reconstituted mice (hu-PBL-SCID) that demonstrated successful engraftment by the presence of serum titers of human immunoglobulin (Ig) were inoculated intraperitoneally with DEN virus serotype 1 (DEN-1). Serial blood samples were taken postinoculation and assayed for virus in C6/36 cells. The identity of all viral isolates was confirmed by an immunofluorescence antibody assay using DEN-1 monoclonal antibody. A total of six experiments were performed using different procedures of reconstitution and infection, and in three of these experiments, DEN-1 virus was recovered from the hu-PBL-SCID mice. In the first successful experiment, DEN-1 virus was recovered on postinoculation day (PID) 24 from blood, spleen, thymus, and lung tissues of one of eight hu-PBL-SCID mice. A second group of eight hu-PBL-SCID mice were inoculated with human monocytes infected in vitro with DEN-1 virus. Virus was recovered from the blood of mice between PID 15 and 23, and from lung tissue of one of these mice. In a third experiment, seven SCID mice were treated initially with anti-asialo GM1 antibody to eliminate natural killer cells, and then were injected simultaneously with a mixture of hu-PBL and DEN-1 virus. Virus was demonstrated in the blood of one mouse on PID 38, and in another mouse on PID 8, 12, 20, 24, and 36. Virus was recovered from lung tissue of the first mouse on PID 85 and from all tissues tested from the second mouse on PID 50. Tissues from the second mouse also were tested by immunostaining, and DEN viral antigen was detected in liver, spleen, kidney and lung sections; human B cells were detected in spleen and lung tissues, and human T cells were detected in lung and brain. The DEN virus—positive mice from all three experiments had been reconstituted with lymphoid cells from the same human donor. None of the 16 nonreconstituted SCID mice inoculated with DEN-1 virus as controls for these three experiments had detectable virus in any tissues. Attempts to detect evidence of DEN-1 virus infection of hu-PBL-SCID mice in three additional experiments using other human donors were unsuccessful. Data derived from these experiments show that hu-PBL-SCID mice can be infected with DEN-1 virus, but the frequency of infection was low. Further studies need to be conducted to better define and control the factors responsible for susceptibility to DEN virus infection in the hu-PBL-SCID mouse before it will be useful as a laboratory model.