Regulatory T cells (T_reg cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b⁺ myeloid cells in recombination-activating gene 1–deficient (Rag1^−/−) recipient mice was needed to prevent the colitis induced by transferred CD4⁺CD45RB^hi T cells. In Il10^−/−Rag1^−/− mice, T_reg cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor–deficient (Il10rb^−/−) T_reg cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T_reg cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T_reg cells to maintain Foxp3 expression.