Intermittent alcohol exposure is a common pattern of alcohol consumption among adolescents and alcohol is known to modulate the expression of the endocannabinoid system (ECS), which is involved in metabolism and inflammation. However, it is unknown whether this pattern may have short-term consequences on the ECS in the spleen. To address this question, we examined the plasma concentrations of metabolic and inflammatory signals and the splenic ECS in early adult rats exposed to alcohol during adolescence. A 4-day drinking in the dark (DID) procedure for 4 weeks was used as a model of intermittent forced-alcohol administration (20%, v/v) in female and male Wistar rats, which were sacrificed 2 weeks after the last DID session. First, there was no liver damage or alterations in plasma metabolic parameters. However, certain plasma inflammatory signals were altered according to sex and alcohol exposition. Whereas fractalkine [chemokine (C-X3-C motif) ligand 1] was only affected by sex with lower concentration in male rats, there was an interaction between sex and alcohol exposure in the TNF-α and interleukin-6 concentrations and only female rats displayed changes. Regarding the mRNA and protein expression of the ECS, the receptors and endocannabinoid-synthesizing enzymes were found to be altered with area-specific expression patterns in the spleen. Overall, whereas the expression of the cannabinoid receptor CB1 and the nuclear peroxisome proliferator-activated receptor PPARα were lower in alcohol-exposed rats compared to control rats, the CB2 expression was higher. Additionally, the N-acyl-phosphatidylethanolamine-specific phospholipase D expression was high in female alcohol-exposed rats and low in male alcohol-exposed rats. In conclusion, intermittent alcohol consumption during adolescence may be sufficient to induce short-term changes in the expression of splenic endocannabinoid signaling-related proteins and plasma pro-inflammatory cytokines in young adult rats with a strong sexual dimorphism. The potential impact of these alterations in early adulthood remains to be elucidated. ; JOURNAL ARTICLE; The present study has been supported by Instituto de Salud Carlos III (ISC-III), RETICS Red de Trastornos Adictivos (RD12/0028/0021) and European Regional Development Funds- European Union (ERDF-EU); GRUPOS UCM-BSCH (UCM 951579), Ministerio de Economía y Competitividad (PI13/02261); Plan Nacional sobre Drogas (049/ 2013); Consejería de Economía, Innovación y Ciencia, Junta de Andalucía and ERDF-EU (CTS- 433); Consejería de Salud y Bienestar Social, Junta Andalucía (PI0228-2013 and PI0823-2012). JS, AS and FJP hold a “Miguel Servet”research contract from ISC-III and ERDF-EU (CP12/03109, CP14/ 00173 and CP14/00212, respectively). FA holds a “Sara Borrell” research contract from ISC-III and ERDF-EU (CD14/00259).