An increased airway response to various bronchocon‐stricting agents is one of the hallmarks of asthma. An interdependence of heredity and environment appears to determine this nonspecific hyperreactivity of the airways. The present study describes the patterns of inheritance of the airway response to a direct mediator of smooth muscle contraction (acetylcholine) in A/J and C3H/HeJ inbred mice and their offspring. The mean airway response to acetylcholine was greater than sixfold higher in A/J mice as compared with C3H/HeJ mice. Two phenotypes were easily distinguished on the basis of airway responses to acetylcholine in the progeny of A/J and C3H/HeJ mice. These two phenotypes were termed HYPERREACTIVE (after the A/J strain) and HYPOREACTIVE (after the C3H/HeJ strain). The observed frequencies of HYPERREACTIVE and HYPOREACTIVE phenotypes in the (A/J × C3H/HeJ) Fl; (C3H/HeJ × A/J) F1 × C3H/HeJ (C3H/HeJ backcross); and the [(A/J × C3H/HeJ) F1 × (C3H/HeJ x A/J) F1] F2 are consistent with a single autosomal recessive gene primarily controlling acetylcholine‐mediated airway responses. This single gene difference in airway response is completely inhibited by atropine and therefore mediated entirely by the muscarinic acetylcholine receptor.— Levitt, R. C.; Mitzner, W. Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice. FASEB J. 2: 2605‐2608; 1988.