To understand better the response of patients with allergic rhinitis to nasal challenge with antigen, we studied the mechanism of priming, that is, the increased clinical response to daily sequential nasal challenges. Ten subjects with ragweed hay fever were challenged four times with increasing doses of ragweed pollen. The first 2 challenge days were separated by 2 weeks, whereas the last three challenges occurred on sequential days. Nasal lavages, performed before and after each nasal challenge, were evaluated for levels of inflammatory mediators and cellular content. In contrast to control days, a significant (p less than 0.05) increase in the number of sneezes occurred on both priming days. Priming was associated with a significant increase in the level of histamine on both priming days, whereas the second priming day was also associated with an increase in TAME-esterase activity, kinins, and prostaglandin D2 obtained after challenge (p less than 0.05 for all). In the lavages before challenge on the priming days, the total number of cells and the number of neutrophils, eosinophils, and alcian blue-positive cells were significantly increased, but in contrast, basal levels of mediators were not. The net increase in the number of alcian blue-positive cells correlated with the net increase in the amount of histamine released on the priming days (r = 0.661; p less than 0.05). These studies suggest that priming results, in part, from increased mediator release from influxing inflammatory cells.