We have recently demonstrated the nocturnal increase in leptin secretion in humans. In the present study we have examined the pulsatile pattern of leptin secretion using two different experimental protocols. The first protocol utilized blood samples withdrawn at 30 minute intervals immediately after meals, at 1 hour intervals between meals, and at 2 hour intervals during the night from 4 lean, 11 obese, and 5 obese NIDDM subjects. Analysis of circulating leptin levels by ULTRA algorithmic program and using matched intra-assay coefficient of variations demonstrated 1 to 7 ultradian oscillations with a mean of 3.25 ± 0.36 (SEM) pulses per 24 hour period (period: 10.0 ± 1.5 hours; mean relative amplitude: 0.52 ± 0.06, n=20). Significant positive correlations were observed for changes in absolute amplitude with body mass index (p<0.025) and fasting leptin levels (<0.0001). In the second series of experiments utilizing 15 minute blood sampling from 10 overnight fasted obese subjects (BMI 35.9 ± 2.0 kg/m²), ultradian oscillations for leptin were more frequent, i.e., 2 to 7 oscillations (4.20 ± 0.59), over a 12 hour duration (period: 3.44 ± 0.49; mean relative amplitude: 0.28 ± 0.03). The number of oscillations over a 12 hour period correlated significantly with BMI (p< 0.001), fasting leptin levels (p< 0.01), and absolute amplitude (p< 0.005) in a 15 minute sampling protocol. In summary, similar to other hormones, ultradian oscillations of leptin are observed in humans, although the physiological significance in relation to obesity or feeding behavior is not yet understood.