After implantation of a biomaterial, an inflammatory response involving macrophages is induced. The behavior of macrophages depends on their phenotype, and by directing macrophage polarization unwanted effects may be avoided. In this study, the possibility to modulate the behavior of macrophages activated by biomaterials was assessed in an in vitro model. Primary human monocytes were seeded on polyethylene terephthalate, polypropylene and polylactic acid yarns, and treated with medications frequently used by patients: rapamycin, dexamethasone, celecoxib or pravastatin. Modulation of the adhering macrophages with rapamycin resulted in a generally pro-inflammatory effect. Dexamethasone caused an overall anti-inflammatory effect on the macrophages cultured on either material, while celecoxib only affected macrophages adhering to polyethylene terephthalate and polylactic acid. Pravastatin increased the pro-inflammatory genes of macrophages cultured on polypropylene and polylactic acid. Pairwise comparison revealed that macrophages adhering to polylactic acid seemed to be more susceptible to phenotype modulation than when adhering to polypropylene or polyethylene terephthalate. The data show that macrophages activated by the biomaterials can be modulated, yet the degree of the modulatory capacity depends on the type of material. Combined, this model provides insights into the possibility of using a medication in combination with a biomaterial to direct macrophage behavior and thereby possibly avoid unwanted effects after implantation.