BALB/c, C57BL6, and C3H/HeN mice were experimentally-infected with porcine circovirus type 2 (PCV2). The mice were tested for their ability to become infected with porcine circovirus type 2 (PCV2) and to develop the hallmark PCV2-associated lymphoid depletion and histiocytic replacement of lymphoid follicles characteristic of postweaning multisystemic wasting syndrome. Since immunostimulation has been shown to increase PCV2-replication in the pig, half of the mice were immunostimulated with keyhole limpet hemocyanin in incomplete Freund’s adjuvant (KLH/ICFA) at the time of PCV2-inoculation. PCV2 inoculation was done twice at 4 and 5 weeks of age by using intramuscular and intranasal routes. Necropsies were performed in 5-day-intervals at 12, 17, 22, 27, 32, and 37 days post PCV2 inoculation. None of the mice developed clinical disease and none of the mice developed PCV2-associated lymphoid lesions. Immunohistochemistry (IHC) and in-situ-hybridization (ISH) for PCV2-antigen/nucleic acids was performed on all tissues of all mice and was negative. PCR was done on pooled tissues and serum samples obtained at necropsy. The majority of the mice (101/111 PCV2 infected mice) were positive for PCV2-nucleic acids in tissue samples. Forty-one percent of the mice (46/111 PCV2 infected mice) were positive for PCV2-nucleic acids in serum samples. There was no difference between treatment groups or lines. This study confirms that mice can be infected with PCV2 and could be important in the epidemiology of PCV2; however, the mouse model may not be useful to understand the pathogenesis of PCV2- associated lesions.