The in vitro production of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by monocytes was examined in patients with insulin-dependent diabetes mellitus (IDDM), in those with noninsulin-dependent diabetes mellitus (NIDDM), and in healthy volunteers. The production of IL-1 and IL-6 by monocytes was significantly lower in IDDM patients than in NIDDM patients and normal subjects whereas the TNF-alpha production by monocytes did not differ between IDDM patients and normal subjects. On the other hand, the TNF-alpha production was significantly higher in NIDDM patients than in IDDM patients and normal subjects. There was a significant correlation between IL-1 and IL-6 concentrations in culture supernatants of monocytes for IDDM patients but not for NIDDM patients and normal subjects. Neither glucose nor insulin showed any stimulatory effect on in vitro production of these monokines. In the serial observation lasting 3-18 months, the monocyte production of IL-1 was found to be consistently reduced in IDDM patients unrelated to the control state of diabetes, suggesting that the reduction of the IL-1 and IL-6 production by monocytes in IDDM patients may be intrinsically affected by immunological defects.