We have previously suggested that ozone (O3)-induced pain-related symptoms and inhibition of maximal inspiration are due to stimulation of airway C fibers (M. J. Hazucha, D. V. Bates, and P. A. Bromberg. J. Appl. Physiol. 67: 1535–1541, 1989). If this were so, pain suppression or inhibition by opioid-receptor agonists should partially or fully reverse O3-induced symptomatic and lung functional responses. The objectives of this study were to determine whether O3-induced pain limits maximal inspiration and whether endogenous opioids contribute to modulation of the effects of inhaled O3 on lung function. The participants in this double-blind crossover study were healthy volunteers (18–59 yr) known to be “weak” (WR; n = 20) and “strong” O3 responders (SR; n = 42). They underwent either two 2-h exposures to air or two 2-h exposures to 0.42 parts/million O3 with moderate intermittent exercise. Immediately after post-O3 spirometry, the WR were randomly given either naloxone (0.15 mg/kg iv) or saline, whereas SR randomly received either sufentanil (0.2 μg/kg iv) or saline. O3 exposure significantly ( P < 0.001) impaired lung function. In SR, sufentanil rapidly, although not completely, reversed both the chest pain and spirometric effects (forced expiratory volume in 1 s; P < 0.0001) compared with saline. Immediate postexposure administration of saline or naloxone had no significant effect on WR. Plasma β-endorphin levels were not related to an individual’s O3responsiveness. Cutaneous pain variables showed a nonsignificant weak association with O3responsiveness. These observations demonstrate that nociceptive mechanisms play a key role in modulating O3-induced inhibition of inspiration but not in causing lack of spirometric response to O3 exposure in WR.