Two different classes of water-soluble fullerene derivatives, detergent-type and sphere-type, were synthesized. The derivatives were evaluated for their biological activities including cytotoxicity, DNA cleavage, and inhibition of HIV protease and other enzymes. Both classes of compounds display generally similar behavior except for their cytotoxicity spectra against several cell lines. The fullerene derivatives bearing N-methylpyrrole were found to be photo-inactive with respect to DNA cleaving activity and cytotoxicity. A study on the kinetics for the inhibition of HIV-protease with detergent type derivative revealed that the compound is a potent fullerene-based HIV protease inhibitor, inhibiting the enzyme activity in a reversible and competitive manner with a K(i) value of 0.32 μM.