A major complication of continuous ambulatory peritoneal dialysis (CAPD) is peritonitis. Increasing the activity of the peritoneal macrophages, the predominant cell type found in the peritoneal cavity, may be a promising treatment for this infection. The effect of 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] on the activity of peritoneal macrophages from CAPD patients and nonuremic controls was studied. 1,25(OH)2D3 had a biphasic effect on superoxide generation in the concentration range of 2.5 10-9 M to 5 × 10-6 M with a peak at 2 × 108 M. The addition of 2 × 10-8 M 1,25(OH)2D3 to nonuremic control macrophages for 24 hours caused a significant twofold increase in superoxide generation in response to phorbol myristate acetate (PMA), from 2.21 + 0.2 to 4.1 + 0.2 nmol/106 mac (P < 0.001), and enhanced the bactericidal activity from 60 + 7% to 85 + 9% (P < 0.005). CAPD patients were divided into two groups: Group A, patients with high peritonitis incidence (HPI); group B, patients with low peritonitis incidence (LPI). Macrophages from HPI patients show a lower bactericidal activity (37 ± 5%) and were not affected by 1,25(OH)2D3 after 24 hours of treatment. The increase in macrophage activity was seen only after three days of incubation with the hormone. Macrophages from this group generated a high amount of prostaglandin E2 (PGE2) during the first 24 hours in culture (7.8 ± 0.52 ng/ml as compared with 0.35 ± 0.03 ng/ml in the controls). Addition of 1,25(OH)2D3 together with indomethacin (10-6 M) enhanced the effect of 1,25(OH)2D3 on the macrophages from these patients even after 24 hours of incubation. However, macrophages from LPI patients behaved similarly to macrophages from control subjects. Incubation of 1,25(OH)2D3 with the macrophages for 24 hours significantly increased superoxide generation from 2.47 ± 0.2 to 3.86 ± 0.35 nmol/106 mac (P < 0.001), and killing activity from 62.5 ± 4 to 83 ± 6% (P < 0.001). The concentration of PGE2 (0.37 ± 0.045 ng/ml) released after 24 hours in culture was similar to that of the control. The addition of PGE2 with 1,25(OH)2D3 to macrophages from LPI patients prevented the increase in macrophage activity caused by 1,25(OH)2D3. These results indicate that PGE2 has a role in modulating the effect of 1,25(OH)2D3 on the activity of peritoneal macrophages from CAPD patients.