AbstractGenetic deficiencies of the hepatic glucose‐6‐phosphatase system, either of the enzyme (G6PC1) or of the glucose‐6‐phosphate transporter (G6PT1), result in fasting hypoglycaemia. Low hepatic G6PC1 activities were previously reported in a few term sudden infant death syndrome (SIDS) infants and assumed to be due to G6PC1 genetic deficiencies. In preterm infants, failures of postnatal activation of G6PC1 expression suggest disordered development as a novel cause of decreased G6PC1 activity in SIDS. G6PC1 and G6PT1 functional and mutational analysis was investigated in SIDS and non‐SIDS infants. G6PC1 hepatic activity was abnormally low in 98 SIDS (preterm, n = 13; term, n = 85), and non‐SIDS preterm infants (n = 35) compared to term non‐SIDS infants (n = 29) and adults (n = 9). Mean glycogen levels were elevated, except in term non‐SIDS infants. A novel G6PT1 promoter polymorphism, 259C → T was found; the − 259*T allele frequency was greater in term SIDS infants (n = 140) than in term control infants (n = 119) and preterm SIDS infants (n = 30). Heterozygous and homozygous prevalence of 259C → T was 38.6% and 7.1%, respectively, in term SIDS infants. In cell‐based expression systems, the presence of − 259T in the promoter decreased basal luciferase activity by 3.2‐fold compared to − 259C. Glucose‐6‐phosphatase latency in hepatic microsomes was elevated (indicating decreased G6PT1 function) in heterozygous and homozygous − 259T states. Delayed postnatal appearance of hepatic glucose‐6‐phosphatase in infants makes them vulnerable to hypoglycaemic episodes and this may occur in some SIDS infants. However, SIDS may be an association of more complex phenotypes in which several genes interact with multiple environmental factors. A UK‐wide DNA Biobank of samples from all infant deaths, with an accompanying epidemiological database, should be established by pathologists to allow cumulative data to be collected from multiple genetic investigations on the same large cohort of samples, with the aim of selection of the best combination of genetic markers to predict unexpected infant death. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.