1. The effects of orally administered LY293111 on ex vivo neutrophil Mac-1 upregulation were determined in a total of 24 healthy male subjects within three study periods. 2. In the first period, eight volunteers received 60 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average ex vivo Mac-1 response of the LY293111 group was 56% of the predose control (95% confidence interval (CI) 44.3 to 67.9%; P < 0.01). The inhibitory effect was maximum at the end of dosing and had disappeared by day 14. 3. In the second period, eight subjects received 120 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average response of the LY293111 group was 70% of the pre-dose control (95% CI 59.7 to 81.0%; P < 0.01). The inhibitory effect was maximum the day following the initial dose and continued throughout the dosing period. 4. In the third period, eight subjects received 200 mg LY293111 or placebo twice daily in 15 total doses over 8 days followed by a 1 week follow-up. Mac-1 upregulation was 64% of pre-dose levels (95% CI 53.8 to 75.1%; P < 0.01) over the course of the study period. The inhibition had disappeared 2 days following the final dose. Alternate neutrophil stimulation by fMLP was not inhibited. 5. No statistically significant inhibition was observed for placebo-treated subjects. 6. No statistically significant differences were apparent between the active dose regimens. 7. The results indicate that orally administered LY293111 is pharmacologically active in humans. Results from this study may be useful in determining dose selection for efficacy trials.