ABSTRACT: Importance:Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. Objective:To assess the efficacy of ?-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Design, Setting, and Participants:This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2?×?2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Interventions:Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (?-cyclodextrin?plus?hydrolyzed ginseng, ?-cyclodextrin?plus?placebo, placebo?plus?hydrolyzed ginseng, or placebo?plus?placebo) for 6 months. All participants received dietetic advice for weight loss. Main Outcomes and Measures:The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. Results:A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive ?-cyclodextrin?plus?hydrolyzed ginseng, 99 were randomized to receive ?-cyclodextrin?plus?placebo, 101 were randomized to receive placebo?plus?hydrolyzed ginseng, and 100 were randomized to receive placebo?plus?placebo. For 200 participants taking ?-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P?=?.51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P?=?.95). Use of ?-cyclodextrin was associated with constipation (16 participants vs 4 participants; P?=?.006) and cough (8 participants vs 1 participant; P?=?.02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P?=?.006). Only 37 of 401 participants (9.2%) experienced these adverse events. Conclusions and Relevance:Although they are safe for use, there was no benefit found for either ?-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Trial Registration:Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.