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Tolerance to the toxic effects of exposure to the organophosphate acetylcholinesterase inhibitor, disulfoton, was induced by giving multiple, sublethal doses of the compound to male rats. Tolerance was judged to have been induced when toxic signs of exposure, including weight loss, were reversed or diminished. Binding of the specific muscarinic radioligand, [3H] quinuclidinyl benzilate ([3H] QNB) to ileal muscle, forebrain, and hindbrain from treated animals was significantly less than the amount bound to tissue from the control animals. Binding of [3H] QNB to heart tissue from tolerant animals was not different from control values. After a typical tolerance-inducing regimen of 7 doses of 2 mg/kg/day disulfoton followed by 4 doses of 3 mg/kg/day, [3H] QNB binding to heart from treated animals was 104% of controls, while binding to ileal muscle, forebrain, and hindbrain was 67, 69, and 77% of control values (p less than .001, .001 and .01), respectively. [3H] QNB binding was not decreased due to competition for binding sites with excess acetylcholine. Neither were decreases due to displacement by disulfoton, as an acute dose of disulfoton (which caused marked inhibition of acetylcholinesterase) did not result in decreased binding. The maximal binding (Bmax) to forebrain of tolerant animals was 56% of control (1.06 vs 1.88 pmol [3H] QNB mg protein-1, p less than 0.01), but no statistically significant change could be seen in equilibrium dissociation constants (Kd, 0.35 vs 0.36 nM). No changes in [3H] QNB binding constants occurred in hearts form tolerant animals. Differences between tolerant and control groups could be seen in [3H] QNB binding to striatum, but no alterations occurred in this brain area in the binding of dopaminergic or gabaergic radiolabels. The data presented in consistent with the hypothesis that cholinergic receptors are involved in organophosphate tolerance.