Systemic inoculation of the interferon (IFN) inducer polyinosinic-polycytidylic polyribonucleotide (poly I:poly C) into CBA/J mice produces a significant decrease in the number of thoracic duct lymphocytes (TDL) collected 6 to 22 hr after injection. The number of TDL is restored to normal levels by 48 to 64 hr. Residual TDL collected during the inhibition period of poly I:poly C treatment showed a phenotypic profile similar to phosphate-buffered saline- (PBS) treated control groups when examined for Lyt-1.1, Lyt-2, Thy-1.2 and Iak surface markers. Interferon is implicated as the mediator of this phenomenon since: 1) Inoculation of exogenous IFN can induce a similar suppression in the number of recoverable TDL. 2) Pretreatment of mice with sheep anti-murine IFN serum can block this effect of poly I:poly C. Similar experiments with vaccinia virus demonstrate that although live virus can partially suppress the TDL output, almost complete suppression is achieved with ultraviolet (UV)-inactivated virus. Vaccinia virus-induced suppression of the number of TDL also appears to be caused by IFN since: 1) UV-inactivated virus induces significantly higher serum levels of IFN in comparison to live virus. 2) The suppression of TDL output by either live or UV-inactivated vaccinia virus can be blocked by pretreatment with anti-murine IFN. These findings suggest that the immunosuppression often associated with viral infections may be at least partially due to a decrease in lymphocyte recirculation mediated by the IFN initially released in response to the virus.