The effect of cyclosporin A (CsA) on host immunity to cutaneous reinfection with the parapoxvirus orf virus was studied in 6-month-old lambs. In control reinfected animals, clinical lesions and viral replication (measured by the presence of vesicular/pustular lesions and viral antigen) in regenerating epidermal cells were at a maximum on day 4 with resolution by day 9. Lesion histology revealed recruitment of T cells, B cells and dermal dendritic cells (DDC) which increased and decreased in parallel with the clinical course of the reinfection. In animals treated with CsA (25 mg/kg/day) 1 day before and for 8 days after reinfection, more severe clinical lesions and viral replication typical of primary infections were recorded and had not resolved by 28 days following reinfection. During CsA treatment, the recruitment of T cells, B cells and DDC was inhibited. With cessation of CsA treatment there was dramatic recruitment of CD4+ T cells followed by DDC then B cells to the lesion site but rapid onset of acquired immunity was not recorded. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of cytokine mRNAs from lesion biopsies showed individual sheep variations. However, interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNAs were detected in the control reinfected animals on days 3 and/or 9 after reinfection but not on these days in animals undergoing treatment with CsA. In the untreated lambs there was an inexplicable lack of IL-2 and IFN-gamma mRNAs on day 6 after reinfection. Tumour necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) mRNAs were unaffected by CsA treatment. The data suggest that CsA abrogates acquired immunity to orf virus reinfection by targetting T-cell lymphokine production.