Subcutaneous injection with certain polyunsaturated fatty acids (PUFA), in particular linoleic acid (C18:2), has recently been shown to prolong the survival of skin allografts in mice and to reduce both primary and secondary cytotoxic responses by isolated spleen cells. In this study we have examined changes in the lymphoid and reticulo-endothelial systems of both grafted and ungrafted mice treated according to the schedules shown to prolong allograft survival. Many of the changes in the lymphoid and reticulo-endothelial systems which can be produced by allografting could also be produced in ungrafted animals by PUFA treatment. These changes included: increased 125IudR uptake by spleen, lymph nodes, and bone marrow, increased spleen and lymph node weight, increased proportion of red pulp and granulocyte precursors in the spleen, and reticulo-endothelial activation as shown by an increased rate of carbon clearance. The combined effects of allografting and C18:2 on peripheral lymph node weight were greater than the effect of either treatment alone, but fell short of the sum of both treatments. Allografting increased 125IudR uptake/unit organ weight, not only in the peripheral lymph nodes, but also in bone marrow, thymus and spleen. When allografted animals were C18:2 treated, this increase was considerably reduced, uptake being little different from that in C18:2 treated ungrafted controls. The number of Θ-positive cells in the spleen was markedly increased by a tumour allograft, but such an increase could not be seen in allografted animals when treated with C18:2. Whilst prolonged C18:2 treatment led to destructive changes in the spleen, immunoinhibition could still be demonstrated after shorter treatments with C18:2 when no gross histological evidence for tissue destruction was apparent. Partial reversibility of inhibition of cytotoxic activity of isolated spleen cells could be demonstrated when treatment was discontinued.