I think there are many reasons why it could help someone, and not just for immune system modulation (although that is one way). The following are unconventional ways I think it could help: It thins the blood (protects against hyper coagulation which occurs in many cases of CFS) It increases the rate at which epinephrine is created (helpful in situations of "central fatigue" which bodybuilders describe much like CFS, but more like central nervous system "burn out" and attributed to high levels of serotonin. The adrenal gland needs large amounts of vitamin C to produce adrenal hormones. The is where the hpa-axis dysfunction component would be helped. It boosts levels of glutathione in Lymphocytes, and boosts many facets of the immune system via many pathways, including increasing Interferon. Furthermore it concentrates in white blood cells, and it's possible you will need much more vitamin C for these white blood cells if you are dealing with a pathogen like EBV or even Lyme It's an antioxidant that will help prevent cellular damage and breakdown of cellular components such as mitochondria Vitamin C lowers cortisol overall, but can also lower the peaks and raise the troughs It increases endothelial nitric oxide. This is an interesting one because I've been seeing some "breakthroughs" and or cures coming from using nitric boosting / mediating supplements Vitamin C lowers histamine. So if you speculate histamines / MAST cell issues, this may help I think many people are turned off by the Dr. Lam "just take vitamin C" theory, but even he may be unsure of all the ways it could work. He may also prescribe doses that are too high. So the key is finding the right dose. Personally I've experienced some very good affects from Vitamin C dosed at 1 gram, 4x a day. I also notice when it seems like I'm too low, I just add another gram and it seems to help turn the brain back on.