Purpose: We evaluated the proliferative response of lymphocytes to phytohemagglutinin P (PHA P), concanavalin A (Con A), and pokeweed mitogen (PWM) during the course of acute pancreatitis. Patients and Methods: Sixty consecutive patients with acute pancreatitis were studied within 48 h of the onset of pain, and 16 of them were also studied 1 month after complete recovery. According to the Atlanta criteria, 21 patients had severe disease and 39 had mild disease. Fifteen healthy subjects and 11 patients with nonpancreatic acute abdomen were studied as controls. In 12 patients with acute pancreatitis the lymphocyte proliferation after stimulation with the three mitogens was also assessed in autologous and heterologous plasma. Results: The lymphocyte proliferative response to optimal doses of PHA P, Con A, and PWM was significantly lower (p < 0.001) in acute pancreatitis patients (mean ± SD; PHA P 74,310 ± 22,960 cpm; Con A 64,669 ± 20,188 cpm; PWM 26,714 ± 6,436 cpm) than in healthy subjects (PHAP Ill,316 ± 12,044 cpm; Con A 96,276 ± 12,327 cpm; PWM 33,957 ± 3,601 cpm). Patients with nonpancreatic acute abdomen had a significantly higher lymphocyte proliferative response to PHA P and Con A than acute pancreatitis patients (PHA P p < 0.002; Con A p < 0.01; PHAP 91,116 ± 22,995 cpm; Con A 77,879 ± 19,083 cpm). In patients with acute pancreatitis, lymphocyte proliferation stimulated with PHA P and Con A was significantly lower (PHA P p < 0.005; Con A p < 0.001) in those with severe disease (PHAP 63,190 ± 15,157 cpm; Con A 52,813 ± 13,324 cpm) than in those with mild disease (PHA P 80,298 ± 24,340 cpm; Con A 71,052 ± 20,490 cpm). In the group of 16 patients studied during the initial phase of acute pancreatitis and 1 month after recovery, lymphocyte proliferation significantly improved after remission of the disease but remained impaired compared with that of healthy subjects. No difference was found in the lymphocyte proliferation of the 12 patients with acute pancreatitis assayed in autologous and heterologous plasma. Conclusions: The peripheral lymphocyte proliferative response to mitogen stimulation in patients with acute pancreatitis was decreased during the early phases of the disease.