The Harderian gland of the lizard Podarcis sicula sicula (Raf) contains connective tissue type mast cells whose numbers vary during the year showing two peaks, one in spring the other in winter. No sex differences are found throughout the year. Thermal and photoperiodic manipulations indicate that only temperature influences mast cell number (MCN) both in winter and in summer but not in spring. In animals exposed to high temperatures in February (but not in May) MCN declined, while exposure to low temperature in July had the opposite effect. Estradiol treatment of the February and April lizards increased MCN, an effect counteracted by the synthetic antiestrogen tamoxifen; in July lizards, this did not occur. In animals exposed to a high temperature in February, estradiol had no effect, as in animals exposed to low temperatures in July. These data suggest that in spring MCN seems to be more responsive to hormonal stimuli rather than external cues (temperature), while in summer MCN is more sensitive to temperature than to hormonal stimuli (estradiol). Both humoral and external factors are concluded to influence mast cell numbers in the Harderian gland of the lizard P. sicula sicula.