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BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs and important posttranscriptional regulators of gene expression. Adipose tissue is a major source of circulating miRNAs; adipose-related circulating miRNAs may regulate body fat distribution and glucose metabolism. OBJECTIVES: We investigated how changes in adipose-related circulating microRNAs-99/100 (miR-99/100) in response to lifestyle interventions were associated with improved body fat distribution and reductions of diabetogenic ectopic fat depots among adults with abdominal obesity. METHODS: This study included adults with abdominal obesity from an 18-mo diet and physical activity intervention trial. Circulating miR-99a-5p, miR-99b-5p, and miR-100-5p were measured at baseline and 18 mo; changes in these miRNAs in response to the interventions were evaluated. The primary outcomes were changes in abdominal adipose tissue [visceral (VAT), deep subcutaneous (DSAT), and superficial subcutaneous (SSAT) adipose tissue; cm(2)] (n = 144). The secondary outcomes were changes in ectopic fat accumulation in the liver (n = 141) and pancreas (n = 143). RESULTS: Greater decreases in miR-100-5p were associated with more reductions of VAT (β ± SE per 1-SD decrease: −9.63 ± 3.13 cm(2); P = 0.0025), DSAT (β ± SE: −5.48 ± 2.36 cm(2); P = 0.0218), SSAT (β ± SE: −4.64 ± 1.68 cm(2); P = 0.0067), and intrahepatic fat percentage (β ± SE: −1.54% ± 0.49%; P = 0.0023) after the interventions. Similarly, participants with greater decrease in miR-99a-5p had larger 18-mo reductions of VAT (β ± SE: −10.12 ± 3.31 cm(2) per 1-SD decrease; P = 0.0027) and intrahepatic fat percentage (β ± SE: −1.28% ± 0.52%; P = 0.015). Further, decreases in circulating miR-99b-5p (β ± SE: per 1-SD decrease: −0.44% ± 0.21%; P = 0.038) and miR-100-5p (β ± SE: −0.50% ± 0.23%; P = 0.033) were associated with a decrease in pancreatic fat percentage, as well as improved glucose metabolism and insulin secretion at 18 mo. CONCLUSIONS: Decreases in circulating miR-99-5p/100-5p expression induced by lifestyle interventions were related to improved body fat distribution and ectopic fat accumulation. Our study suggests that changes in circulating adipose-related miR-99-5p/100-5p may be linked to reducing diabetogenic fat depots in patients with abdominal obesity. This trial was registered at clinicaltrials.gov as NCT01530724.