Objective: Colchicine is known to reduce inflammation and improve endothelial cell function and atherosclerosis in obesity, but there is little knowledge of the specific circulating leukocyte populations that are modulated by colchicine. Methods: A secondary analysis of a double-blind randomized controlled trial of colchicine 0.6 mg or placebo twice daily for 3 months on circulating leukocyte populations and regulation of the immune secretome in 35 adults with obesity was performed. Results: Colchicine altered multiple innate immune cell populations, including dendritic cells and lymphoid progenitor cells, monocytes, and natural killer cells when compared with placebo. Among all subjects and within the colchicine group, changes in natural killer cells were significantly positively associated with reductions in biomarkers of inflammation, including cyclooxygenase 2, pulmonary surfactant-associated protein D, myeloperoxidase, proteinase 3, interleukin-16, and resistin. Changes in dendritic cells were positively correlated with changes in serum heart-type fatty acid-binding protein concentrations. Additionally, colchicine treatment reduced cluster of differentiation (CD) CD4+ T effector cells and CD8+ T cytotoxic cells. Conversely, colchicine increased CD4+ and CD8+ T central memory cells and activated CD38High CD8+ T cells. Changes in CD4+ T effector cells were associated with changes in serum heart-type fatty acid-binding protein. Conclusions: In adults with obesity, colchicine significantly affects circulating leukocyte populations involved in both innate and adaptive immune systems along with the associated inflammatory secretome.