In a double-blind trial 119 adults were randomly assigned to receive daily sprays of placebo (N = 30) or rIFN-alpha Con1 3 MU (N = 29), 9 MU (N = 30), or 30 MU (N = 30) per day for 25 consecutive days. Fifty-nine subjects were removed from treatment because of abnormal nasal exams (N = 56) or irritative symptoms (N = 3). The fraction of drop-outs in the placebo group (30%) was significantly different (P less than 0.05) from that in the 3 MU (55%), 9 MU (57%), or 30 MU (67%) groups. Nasal mucosal biopsies collected 1-2 days after completing spray use detected moderate or marked lymphocytic infiltration in 10% of placebo (N = 10), 90% of 3 MU (N = 9), 85% of 9 MU (N = 13), and 70% of 30 MU (N = 10) subjects (P less than 0.05, placebo vs each rIFN-alpha Con1 group). All 3 dose levels of rIFN-alpha Con1 were associated with significant clinical and histopathologic signs of nasal irritation. The findings suggest that intranasal rIFN-alpha Con1 does not have a more favorable therapeutic index than rIFN-alpha 2 and that the risk of nasal irritation relates more closely to the anti-viral activity than the protein content of the rIFN-alpha administered.