Some organochlorine pesticides (OCPs) are suspected of modulating the endocrine systems of humans. Aspects of neuro-endocrine system modulation include interactions such as agonism or antagonism of estrogen receptor (ER) binding. However, less is known about their interactions with other nuclear receptors (NRs). The objectives of this study were to determine and compare the ability of p,p'-dichlorodiphenylethane (p,p'-DDE), p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), hexachlorobenzene (HCB) and r-hexachlorocyclohexane (r-HCH) to interact with ERalpha, androgen receptor (AR), progesterone receptor (PR) and estrogen-related receptor (ERRgamma) using a set of recombined yeast strains expressing beta-galactosidase, under control of ERalpha, AR, PR or ERRgamma. The results showed that p,p'-DDE was an ERalpha agonist, AR and PR antagonist (PR>AR), while p,p'-DDT was an ERalpha agonist and AR antagonist. HCB and r-HCH were antagonists for AR and ERRgamma, while r-HCH was a PR antagonist and a weak antagonist of ERRgamma, and was able to reverse the ERRgamma inhibition induced by 4-hydroxytamoxifen. All the results suggested that, for the tested OCPs, their ability to act as endocrine disruptors involves more than one mechanism, their (anti-)agonistic effects on different receptors should not be overlooked, and the potential for additive or synergistic effects must be taken into consideration in the risk assessment process.