Of central importance to tissue engineering and drug delivery is identifying polymer parameters that increase or decrease specific cytokines in response to biomaterials. In this study, we have interrogated the effects of material descriptors and material characteristics on pro-inflammatory, pro-angiogenic, and naïve macrophages using polymeric particles (∼600 nm), functionalized with 13 different moieties. We characterized tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) secretion for the three macrophage populations and used the quantitative structure–activity relationship method (QSAR) to accurately predict cytokine secretion for the different macrophage phenotypes. The findings presented here demonstrate that altering cellular responses to polymers can be achieved through exploiting material parameters. For pro-inflammatory macrophages, polarity and the ability to hydrogen bond appear to significantly impact TNF-α secretion while charge impacted pro-angiogenic macrophages. Naïve cells were impacted by charge in a similar manner as the pro-angiogenic cells; however, hydrophilicity also increased TNF-α secretion in these cells. For IL-10 secretion, hydrogen bonding was very negatively correlated with pro-inflammatory cells, whereas it was positively correlated with pro-angiogenic cells.