Diabetes is reaching epidemic proportions worldwide. The insufficiency of conventional treatments to cope with this burden has coincided with a dramatic rise in the use of herbs. This has prompted calls for proof of their safety and efficacy. Ginseng is one of the most popular herbs. Whether the glycemic lowering effects we observed repeatedly with a single batch of American ginseng are reproducible is unknown. It is also unclear whether ginsenosides (steroidal glycosides), the principal active components, are mediators. To answer these questions, a series of acute, blinded, placebo-controlled clinical studies was conducted to assess the effect of increasing ginsenoside variability across ginseng source parameters of progressively greater ginsenoside variability (batch, preparation, variety, and species) on postprandial carbohydrate metabolism. A 75g-oral-glucose-tolerance-test (75g-OGTT) protocol was followed with ginseng administered 40min before the start of the test and blood drawn at -40, 0, 15, 30, 45, 60, 90, and 120min. In the first study, while our original efficacious batch of American ginseng lowered plasma glucose indices (P < 0.05), a second batch with a depressed ginsenoside profile including a low protopanaxadiol:protopanaxatriol-ginsenoside [PPD:PPT] ratio was ineffective. In the consolidated second and third studies, another species, Asian ginseng, with marked inversions in its ginsenoside profile (PPD:PPT < 1) had null and opposing effects on plasma glucose indices. In the fourth study, in which effects on plasma glucose and insulin regulation were assessed across the range of ginseng source parameters by comparing 8 of the most popular ginseng types, a third batch of American ginseng lowered, while Asian, wild-American, and Siberian ginsengs raised plasma glucose compared with placebo (P < 0.05). Stepwise-multiple-regression models assessed the PPD:PPT ratio as the sole albeit weak independent predictor (P < 0.05). Taken together, glycemic variability appeared secondary to variability in the ginsenoside profile, particularly the PPD:PPT ratio. To understand the implications, a meta-analysis assessed the coefficient-of-variation (CV) of ginsenosides across the same parameters of ginseng source. As the CV of ginsenosides was found to be as high as the experimental variability achieved in the clinical studies, it was concluded that the effects on postprandial glycemic regulation might be equally highly variable. A basis for standardization is needed.