The use of nutritional supplements (NS) with the intention of improving health and delaying age-related chronic disease is a common practice among older adults; however, randomized controlled trials have yielded mixed results regarding the likelihood that these NS provide true health benefits. We reviewed the findings of these studies regarding the effects of NS of folic acid, vitamin B(12), vitamin B(6), and omega-3 fatty acids on health outcomes in older adults. Our conclusions include the following: Supplements of the B vitamins folate, B(12) and B(6) have been studied with regards to primary and secondary prevention of a number of major age-related chronic diseases, including cardiovascular disease (CVD), stroke, cognitive decline, and cancer. While there are some encouraging findings with regards to stroke, depression, and macular degeneration (although in only one study in the latter case), there is little evidence of benefit of B vitamin NS for delaying CVD or age-related cognitive changes. In the few cancer-related studies, the evidence of benefit is coupled with concerns about enhancing the growth of existing undiagnosed cancers. In contrast, clear health benefits have been shown with modest increases in consumption of fatty fish or fish oil supplements, including a reduction in the risk of sudden cardiac death. In addition, there is evidence that high dose fish oil supplements may lower serum triglyceride levels.