An increasing body of evidence shows a role for macrophages and monocytes (as their precursors) in hypertension, but with conflicting results with regard to whether they are protective or harmful. Therefore, we systematically reviewed the effect of macrophage interventions on blood pressure in animal models, to explore which factors determine the blood pressure increasing vs. decreasing effect. A search in PubMED and EMBASE yielded 9620 records, 26 of which were included. Eighteen studies (involving 22 different experiments (k = 22)) performed macrophage depletion, whereas 12 studies specifically deleted certain macrophage proteins. The blood pressure effects of macrophage depletion were highly various and directed toward both directions, as expected, which could not be reduced to differences in animal species or methods of hypertension induction. Prespecified subgroup analysis did reveal a potential role for the route in which the macrophage-depleting agent is being administrated (intraperitoneal vs intravenous subgroup difference of P = 0.07 (k = 22), or P < 0.001 in studies achieving considerable (ie, >50%) depletion (k = 18)). Along with findings from specific macrophage protein deletion studies-showing that deletion of one single macrophage protein (like TonEBP, endothelin-B, EP4, NOX-2 and the angiotensin II type 1 receptor) can alter blood pressure responses to hypertensive stimuli-the indication that each route has its specific depletion pattern regarding targeted tissues and macrophage phenotypes suggests a determinative role for these features. These hypothesis-generating results encourage more detailed depletion characterization of each technique by direct experimental comparisons, providing a chance to obtain more knowledge on which macrophages are beneficial versus detrimental in hypertension development. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.