Nonspecific bronchial hyperreactivity (NSBHR) has been observed in patients who have undergone lung transplantation, but studies have provided conflicting reports as to the incidence and significance of this finding. To delineate more clearly the natural history of NSBHR after lung transplantation, data from 111 consecutive patients undergoing double lung transplantation between February 1988 and May 1994 were reviewed. Methacholine challenge testing was requested in conjunction with regular postoperative follow-up. Among 60 patients tested at 3 mo, 18 (30%) had a positive methacholine challenge; at 6 mo, the incidence was 14 of 59 (24%). Of 21 patients for whom complete testing was performed for 12 mo or longer, 13 (62%) had exclusively negative challenges. Patients with a positive challenge at 3 mo were significantly more likely to develop bronchiolitis obliterans syndrome (BOS) (p < 0.006). Mean time to development of BOS was 16.9 mo in the group with positive challenges versus 43.9 mo for those with negative challenges. We conclude that increased NSBHR is a common, but by no means universal, finding after lung transplantation. Furthermore, early positive methacholine challenges are associated with development of BOS. We hypothesize that NSBHR may represent an early marker of chronic rejection in these patients.