Frequent blood sampling from males rats was used to study hypothalamic-pituitary-adrenal (HPA) axis activation during arthritis and its association with diminished responses to acute psychological stress. In control rats, corticosterone release occurred in a series of 13 ± 1 pulses per 24 h. Induction of arthritis by Mycobacterium-adjuvant injection initially increased the rate of hormone release within each pulse and, by day 14 postinjection, when hind-paw inflammation was established, caused a marked increase in pulse frequency to 22 ± 1 per 24 h leading directly to elevated circulating corticosterone levels. In both control and adjuvant-treated rats, there was a marked response to a 10-min noise stress when the stimulus coincided with a rising or interpulse phase of the endogenous corticosterone rhythm. However, when the noise stress coincided with a falling phase of this rhythm, the response was greatly diminished. Since corticosterone pulse frequency was markedly increased and hence interpulse interval decreased by day 14, there was an increased probability of the noise stress occurring during the nonstress responsive falling phase of the corticosterone secretory cycle. As a result, the group mean response to noise stress was significantly smaller in the arthritic than the controls (70.2 ± 9.2 versus 107.8 ± 13.0 ng/ml, respectively). In contrast to the differential response to noise stress, all rats showed similar responses to the acute immunological challenge with i.v. lipopolysaccharide. Thus, altered basal pulse frequency is a major factor influencing HPA activation during acute psychological stress.