Adiponectin and high-density lipoprotein cholesterol (HDL-C) are negative predictors for cardio-metabolic disorders. This study explored adiponectin's role in predicting multiple metabolic syndrome components (multi-MetSC) in subjects with extremely high HDL-C levels overall and by sex. We enrolled adults with extremely high HDL-C levels (≥90 mg/dL) in general health checkups and compared adiponectin levels in subjects with and without multi-MetSC. Among 274 subjects (median 44 years, female 79.6%), 19 (6.9%) had a multi-MetSC. The adiponectin level was significantly lower in subjects with multi-MetSC than without (females: 9.2 [6.2-13.3] vs. 12.0 [9.7-15.9] µg/mL, p = 0.039; males: 6.9 ± 2.4 vs. 10.0 ± 5.2 µg/mL, p = 0.013). The optimal cutoff values to predict multi-MetSC were 9.7 µg/mL (sensitivity 64%, specificity 74%) in females and 9.6 µg/mL (sensitivity 100%, specificity 44%) in males. Compared with the high adiponectin group, the low group revealed higher fasting glucose in females and higher waist circumference, visceral fat area, and HDL-C levels in males. Multiple logistic regression analysis confirmed adiponectin as an independent predictor of multi-MetSC (OR 0.85, 95% CI 0.71-0.97). Adiponectin could be a potential biomarker for multi-MetSC in general health checkup subjects with extremely high HDL-C levels. There were sex differences in the metabolic risk factors between low and high adiponectin groups.