This paper describes studies performed with ERA-63 a low molecular weight pharmaceutical with intended immunomodulatory effects. Since this compound was also known to have estrogenic activity a non-conventional approach was taken in order to differentiate between estrogenic and non-estrogenic-induced immunomodulatory effects. EE was included not only for qualitative comparison (hazard identification) between immunomodulatory effects but also, in case of similar effects, to facilitate the extrapolation of the findings in the rat to anticipated effects in humans. After 28 days of treatment with dosages ranging from pharmacological up to clearly toxic levels for both compounds the immunotoxic potential was assessed by performing a T cell-dependent antibody response and a host resistance assay in rats. Selected ERA-63 dose levels (0.167-0.2, 1.67-2 and 16.7-20 mg/kg) were expected to have comparable estrogenic activity to respective EE dose levels (0.05, 0.5 and 5 mg/kg). General toxicity parameters reflecting estrogenic activity (i.e. decreased body- and organ weights of thymus and testis, and increased bilirubin and GGT levels) confirmed the comparable estrogenic activity for both compounds at the dose levels tested. Together with the comparable estrogen-related immune suppression (i.e. decreases in specific antibody responses and an increased susceptibility for Listeria monocytogenes infects) for both compounds, this indicates that available clinical data for EE facilitates the human risk assessment of ERA-63. © 2008 Elsevier Ireland Ltd. All rights reserved.