Effects of various derivatives ofα-tocopherol (VE) and coenzyme Q (CoQ) on superoxide (O2*-) generation of neutrophils and protein kinase C (PKC) activity were examined. VE and CoQ8inhibited O2*-generation of neutrophils stimulated by a protein kinase C mediated process monitored by cytochrome c reduction and spin trapping methods. The inhibitory action was observed not only withα-tocopherol, but also withβ-,γ-, dL-tocopherols and with tocol which is a chemical similar to VE but lacking methyl groups on the chromanol ring structure and which is not a radical scavenger. By con trast, no inhibition was observed with 2-carboxy-2,5,7,8-tetramethyl-6-chromanol (CTMC, trolox) or 2,2,5,7,8,-pentamethyl-6-chromanol (PMC) which are water soluble VE derivatives having radical scavenging activity. Compounds having a similar isoprenoid chain, such as CoQ, also have inhibitory activity on PKC-dependent O2*-generation of neutrophils. The inhibitory activity of CoQ derivatives is dependent on the length of the unsaturated isoprenoid chain. CoQ derivatives having 16,24 and 32 carbon isoprenoid chains corresponding to CoQ4,6, and 8 inhibited O2*-generation but 4 and 40 carbon isoprenoid chains corresponding to CoQ2 and 10 had no inhibitory activity on O2*-generation. Alpha-tocopherol and CoQ inhibited PKC activity but the ID50for O2*-generation and PKC activity was different for each compound. However, no direct relationship between VE content and O2*-generation of neutrophils was observed. These results suggest that isoprenoids of VE and CoQ participate in the inhibition of the NADPH oxidase activation system through modulation of the neutrophil membrane probably by the inhibition of PKC.