Background: Sudden unexpected infant death (SUID) remains the leading cause of postnatal mortality in many countries. French and international guidelines recommend a thorough examination with toxicology studies. Objectives: The main objective was to determine the prevalence of toxic detection and positive analyses. The secondary objectives were to describe the different toxics and compare children with positive (Tox+) and negative results (Tox-) with other SUID risk factors. Design and methods: We used the data registered from May 2015 to December 2018 by the French national SUID registry (OMIN). It collects data for all SUID cases admitted to any of the 35 participating French SUID referral centers. Results: Of the 624 SUID cases registered in the OMIN, a post-mortem toxicological analysis was performed in 398 infants. Thirty-six patients (9%) were positives for expected (Etox+ (n = 19 [53%], e.g., resuscitation drugs, regular treatments) and unexpected (UTox+) (n = 17 [47%]) toxics. The unexpected toxics were opioids (n = 8), cannabis (n = 4), cocaine (n = 3), cotinine (n = 2), carbon monoxide (n = 2), caffeine (n = 2), alcohol (n = 1) and GHB (n = 1). UTox + infants had a different seasonal distribution (p = .03), a higher incidence of inappropriate sleeping position and bedding at the time of death (respectively OR 3.8, p = .037 - OR 5.4, p = .026); inadequate body hygiene (OR 10.6, p = .0005), a younger maternal age (p = .045) and a higher rate of maternal drug abuse (OR 21.9, p = .0008). Conclusion: The high rate of positive results warrants routine toxicology testing. The imputability of identified molecules is complicated by the presence of other known risk factors for SUID.