P2X7 receptor activation is involved in a number of pro-inflammatory responses in macrophages and other immune cells. Their expression can be positively modulated with lipopolysaccharide (LPS) and TNFalpha, reinforcing their role during inflammation. We investigated the effect of substances capable of recruiting macrophages into the peritoneal cavity of mice (mineral oil and thioglycolate) on P2X7 receptor expression and function, addressing whether these stimuli can interfere with multinucleated giant cell (MGC) formation, ATP-induced apoptosis, plasma membrane permeabilization and nitric oxide production. It was demonstrated that mineral oil treatment reduces P2X7-dependent MGC formation, whereas thioglycolate treatment does not. Mineral oil treatment reduced P2X7 receptor expression, down-modulating ATP-induced apoptosis, permeabilization and nitric oxide production. In conclusion, mineral oil down modulated P2X7 expression and consequently P2X7-associated phenomena, but thioglycolate did not. These effects might be associated with the unpleasant side effects already described during long-term administration of mineral oil for cosmetic purposes or as a laxative and could be useful in understanding the mechanism of recycling and modulation of P2 receptors present in other situations of immunopathological interest.