The popliteal lymph node (PLN) assay was proposed to study a panel of drug-induced clinical manifestations, e.g. lupus syndrome, serum sickness-like disease, lymphadenopathy, scleroderma-like reaction, the mechanism of which was suggested as being similar to a graft-versus-host (GvH) reaction, hence the term GvH-like reaction. This assay can readily be performed in either the mouse or rat. The commonest endpoint is PLN weight, but cellularity and lymphocyte-phenotype analysis can also be determined. Experiments so far show that most drugs and chemicals known to induce such complications in man can be detected by the PLN assay and false-positive responses are extremely few. Interestingly, preliminary results indicate that cimetidine, an immuno-enhancing agent, can increase the response to phenytoin, a positive reference compound in the PLN assay. Thus, in addition to predicting those drugs with the capacity to induce GvH-like reactions and investigating the mechanism involved, the PLN assay may also prove useful in the pre-clinical assessment of immunomodulating agents.