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Circulating white blood cell (WBC) and platelet (PLT) counts are widely available and inexpensive cellular biomarkers of systemic inflammation and have been associated with a risk of cardiovascular disease, cancer, and mortality. Melatonin may reduce systemic inflammation through its direct and indirect antioxidative effect; however, the associations of melatonin secretion with systemic inflammation remain unclear. In this cross-sectional study on 1088 elderly individuals (mean age, 71.8 years), we measured overnight urinary 6-sulfatoxymelatonin excretion (UME) and WBC and PLT counts as indices of melatonin secretion and systemic inflammation, respectively. UME was naturally log-transformed for linear regression models because of skewed distribution (median, 6.8 μg; interquartile range, 4.1–10.6 μg). Univariate models revealed that higher log-transformed UME levels were significantly associated with lower WBC and PLT counts (P = 0.046 and 0.018). After adjusting for potential confounding factors significantly associated with WBC or PLT counts, higher log-transformed UME levels were significantly associated with lower WBC and PLT counts (WBC: β, −0.143; 95% confidence interval, −0.267 to −0.020; P = 0.023; PLT: β, −6.786; 95% confidence interval, −12.047 to −1.525; P = 0.012). Furthermore, the adjusted mean differences in WBC and PLT counts between the lowest and highest UME tertile groups were 0.225 × 109/L and 9.480 × 109/L, respectively. In conclusion, melatonin secretion was significantly and inversely associated with WBC and PLT counts in the general elderly population. The associations were independent of several major causes of systemic inflammation, including aging, obesity, smoking, hypertension, diabetes, and physical inactivity.