Engineered fullerenes are widely integrated into several commercial and medical products and are now also being recognized as byproducts of many industrial activities. For most applications fullerenes have to be chemically modified. Surface modification of fullerenes can potentially impact their effect on biosystems. The purpose of the current study was to establish criteria to correlate fullerene structure to biological responses. We report studies of cellular responses induced by three different types of fullerenes that provide varying chemical and physical properties such as electronic behavior, solubility, and degree of agglomeration. Using a systematic and multipronged approach for material characterization and employing critical biological endpoints, we determined the impact of the physicochemical properties of fullerenes on cellular interactions. We examined the ability of these fullerenes to regulate intracellular oxidative stress, necrosis and apoptosis in human monocytic THP1 cells. Results indicate that the carboxylate derivatization of fullerenes was the determining factor in their ability to induce apoptosis. In contrast, the dispersion characteristics of fullerenes were found to be more relevant when considering their redox function. We also established a significant role for functionalization-dependent fullerene-regulation of the caspase proteases in the elicited responses. In addition, there was a notable increase in the level of several anti-oxidant enzymes. Collectively, the results clearly indicate that the physicochemical properties of fullerenes significantly influence the elicited biological response, thus impacting future applications. This study is an initial effort to lay the groundwork for routine correlation and predictive analysis on engineered fullerenes, thus expediting their use.