Background: Electronic cigarettes, also known as "cigs," are gadgets created to provide nicotine through a vaping solution rather than smoke and without the burning of tobacco. E-cigarettes are aggressively promoted as consumables among people who want to live healthier lives and are seen as a safer alternative to cigarettes. Aim: To assess structural changes in the adrenal cortex of adult male albino rats and explore effect of withdrawal of electronic cigarette. Material and Methods: 30 adult male rats weighting 150-230 g which were purchased from the Animal House of the Faculty of Medicine, Zagazig University. The animals will be divided equally into 3groups. Each one contains10 rats as follows: Group (1): (control group); which contain ten rats that will be exposed to fresh air for 28 days to measure normal basic parameters. Group (II): (E- cig treated group); which contain ten rats that will be exposed to 1ml/day of E- liquid containing 18 mg/ml Nicotine by inhalation of the E-cig aerosol by E- cig device for consecutive 5 days/ week for 28 days. Group (III): (withdrawal group); which contain ten rats which will be exposed to 1ml/day of E- liquid containing 18 mg/ml Nicotine by inhalation of the E-cig aerosol by E- cig device for 5 consecutive days/ week for 4 weeks and then will be left without exposure for another 4 weeks. Results: E-cigarette has hazardous effects on histological structure of adrenal gland cortex as disturbance of zona glomerulosa & fasciculata with corrugated capsule. Also, Zona reticularis cells showed dark condensed nuclei with many blood sinusoids which is dilated and congested. Also, there were significant increase in adrenal gland weight with elevation of MDA level & reduction of SOD level and also increased the level of cortisol and aldosterone in the group treated with E-cig. Moreover, Caspase 3, COX II immune-expression percent area and the number of CD44 +ve cells were significantly increased in treated group. Conclusion: Exposure of adult male albino rats to E-cigs caused histopathological alterations in the adrenal cortex structure with great improvement in its histological structure and biochemical activity after its withdrawal.