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Objective. The objective of this study was to evaluate the effects of early digestive tract decontamination on the severity of acute-on-chronic lithium poisoning (acute poisoning in patients under long-term therapy). Materials and methods. This was an observational and retrospective study of acute-on-chronic lithium overdoses recorded by the Angers Poisons and Toxicovigilance Centre between February 2006 and September 2010. The cases of overdose were divided into two groups: those undergoing early decontamination (by sodium polystyrene sulphonate and/or whole bowel irrigation) and those in whom decontamination was delayed (> 12 h) or not performed. Severity was assessed using the Poisoning Severity Score (PSS). Results. Fifty-nine patients met the inclusion requirements, 15 of whom were decontaminated at an early stage. The mean age of the patients did not differ statistically between the two groups (49 vs. 44 years, p = 0.25). The estimated ingested doses in the early decontaminated and comparison groups were 12.75 and 12.73 g, respectively (p = 0.9), and the PSSs during the first 12 h were 0.8 and 0.69 (p = 0.32). Those patients who were early decontaminated had an overall lower PSS (1.07 vs. 1.79; p = 0.001), maintained a higher GCS (14.93 vs. 13.3; p = 0.038), and their highest measured serum lithium levels were much lower (2.39 vs. 4.08 meq/L; p = 0.001) than those in the comparison group. All patients who received early digestive tract decontamination subsequently recovered. Under multivariate analysis, undergoing early digestive tract decontamination was significantly associated with a lower risk of severe poisoning (OR, 0.21; 95% CI, 0.04-0.99; p = 0.049), regardless of the lithium dose ingested or the serum lithium level. Conclusion. Our results thus highlight the usefulness of early digestive tract decontamination. This technique was statistically associated with a reduction in the severity of acute-on-chronic lithium poisoning at a given ingested dose and serum lithium level.