The pineal gland, through its principal hormone melatonin, is able to modulate different immune functions. We have previously demonstrated that exogenous melatonin induces a significant enhancement of murine antibody-dependent cellular cytotoxicity (ADCC). In order to determine whether the pineal gland plays a physiological role in ADCC regulation, we studied the influence of neonatal pinealectomy on this activity. The results presented here indicate that ablation of the pineal gland during the first week of life significantly reduces ADCC levels in adult mice. This impairment appears around 60 days of age, suggesting that sexual hormones may be involved in the pineal effect. Moreover, the administration of melatonin to pinealectomized mice restores ADCC levels regardless of the hour and seasonal time of injection. On the basis of the data reported here, a physiological regulation of ADCC by the pineal gland can be assumed.