We studied the role of T cells in the regulation of C3 or C4 production by monocytes. While cocultured T cells reduced C3 production, they enhanced C4 production by monocytes in a number-dependent manner. Interleukin-2 enhanced these effects of T cells on C3 and C4 production, indicating that activated T cells had greater effects on complement production by monocytes. CD4+ T cells had greater effects than those of CD8+ T cells on the C3 or C4 production by monocytes, indicating that CD4+ T cells were mainly involved in the regulation of C3 and C4 production by monocytes. T-cell-conditioned medium (T-CM) also decreased C3 and enhanced C4 production, but the effect of T-CM on C3 and C4 production was less remarkable than that of T cells. T cells separated by transwell inserts from monocytes had similar effects as those of T-CM on complement production. Anti-IFN-gamma antibody completely blocked the suppressing effect on C3 production and partially blocked the stimulating effect of T cells on C4 production. These results indicate that T cells regulate C3 or C4 production by monocytes via IFN-gamma as a humoral factor. Moreover, the stimulating effect of T cells on C4 production was partially blocked when monocytes and T cells were incubated with anti-CD2, anti-LFA-1, and anti-HLA-DR antibodies, and anti-CD2 partially blocked the suppressing effect of T cells on C3 production by monocytes. These results indicate that T cells modulate the C3 and C4 production by monocytes not only via a humoral factor but also via a direct interaction with monocytes.