There are marked differences in the clinical expression of diseases associated with porcine circovirus type 2 (PCV2) in the field. The objective of this study was to compare the sequences and pathogenicity of PCV2 isolates from field cases with and without PCV2-associated lesions. Forty-two specific-pathogen-free (SPF) pigs were assigned randomly to three groups of 14 pigs each. At 7 weeks of age, group 1 pigs were mock-inoculated with saline, group 2 pigs were inoculated with PCV2-4838 (isolated from a pig with no evidence of PCV2-associated lymphoid lesions) and group 3 pigs were inoculated with PCV2-40895 (isolated from a pig with PCV2-associated lymphoid lesions and disease). The PCV2-4838 and PCV2-40895 isolates shared approximately 98.9 % nucleotide sequence identity across the entire genome. A total of nine amino acid changes in ORF2 and two amino acid changes in ORF1 were identified between the two isolates. PCV2-4838-inoculated pigs had significantly more genomic copy numbers of PCV2 in their sera at 7 days post-inoculation (p.i.) (P<0.0001) and significantly fewer genomic copy numbers at 14, 21 and 28 days p.i. (P<0.05) compared with pigs inoculated with the PCV2-40895 isolate. Microscopic lesions in lymphoid tissues were significantly less severe (P<0.05) and the amount of PCV2 antigen associated with these lesions was significantly lower (P<0.05) in pigs inoculated with PCV2-4838. The results of this study suggest that PCV2 isolates from the USA differ in virulence in an SPF pig model.