Leukopenia, in particular lymphopenia, is a characteristic early event during classical swine fever (CSF). This was the case in both highly virulent (CSF virus (CSFV) strain Brescia) and moderately virulent (CSFV Uelzen) infections. The leukopenia involved leukocyte sub-populations in a disparate manner, with B-lymphocytes, helper T-cells and cytotoxic T-cells being the most affected. Depletion of lymphocyte sub-populations occurred 1-4 days before virus could be detected by RT-PCR in the serum. With the virulent Brescia virus, depletion was evident by 2 days post-infection (p.i.) but not until 3 days p.i. with an equivalent dose of the low virulent Uelzen strain. A lower (1000-fold) dose of the latter virus delayed these kinetics. gammadelta-TCR(+) T-cells were also reduced, but more so with the virulent Brescia infection. The final level of B-and alphabeta-T-cell lymphopenia was similar for all animals, including those infected with the lower virus dose. AnnexinV staining revealed that cell viability was clearly diminished, particularly interesting, considering the clinical differences between infections by Brescia and Uelzen viruses. It was the time p.i. and rate of appearance of dying cells which was more rapid in the virulent Brescia infections. Interestingly, the repeated blood sampling resulted in depletion of some leukocyte populations also in non-infected control animals. Particularly neutrophils and NK cells, and to a lower extent CD4(+), CD8(+) T-lymphocytes and B-lymphocytes were affected. Taken together, the data show that the alphabeta-T-lymphocyte subsets are particularly susceptible to modulation during the acute phase of CSF, being detectable before the onset of viraemia. The pathogenic mechanism therein would involve indirect virus-host interactions, probably originating from the site of primary infection, rather than a direct effect of the virus or viral protein. Furthermore, these characteristics offer an explanation for the retardation of the cellular and humoral immune response observed during classical swine fever.