The effect of NO2 exposure and human susceptibility to respiratory virus infection was investigated in a placebo-controlled, randomized, double-blind trial conducted in an environmentally controlled research chamber over 3 yr. Healthy, nonsmoking, young adult volunteers who were seronegative to influenza A/Korea/82 (H3N2) virus were randomly assigned to breathe either filtered clean air (control group) or NO2 for 2 h/day for 3 consecutive days. The NO2 concentrations were 2 ppm (Year 1), 3 ppm (Year 2), and 1 or 2 ppm (Year 3). Live, attenuated cold-adapted (ca) influenza A/Korea/82 reassortant virus was administered intranasally to all subjects immediately after the second exposure. Only one of the 152 volunteers had any symptoms; this person had a low grade fever. Pulmonary function measurements and nonspecific airway reactivity to methacholine were unchanged after NO2 exposure, virus infection, or both. Infection was determined by virus recovery, a fourfold or greater increase in serum or nasal wash influenza-specific antibody titers, or both. The infection rates of the groups were 12/21 (2 ppm NO2) versus 15/23 (clean air) in Year 1, 17/22 (3 ppm NO2) versus 15/21 (clean air) in Year 2, and 20/22 (2 ppm) and 20/22 (1 ppm) versus 15/21 (clean air) in Year 3. Each group exposed to 1 or 2 ppm NO2 in the last year became infected more often (91%) than did the control group (71%), but the differences were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)