Background. Serotonin is a good candidate for major depression. We attempted to replicate the study by Caspi and colleagues [Science (2003) 301, 386-389] which reported a significant interaction between serotonin transporter (5-HTTLPR) genotype and stressful life events when predicting major depression. Method. We typed the serotonin promoter 5-HTTLPR gene in 1206 male and female twins aged 19-78 years (mean = 39, S.D. = 11). A DSM-IV diagnosis of major depression was available for 1199 twins. Most of these twins had participated in a 1988-1990 study which included a stressful life events inventory and self-report measure of depression based on the SCL-90 and DSSI/sAD. Complete 5-HTT genotype and life events data, self-report symptoms and major depression diagnoses were available for 1091 subjects. We regressed categorical and ordinal measures of depression onto stressful life events and genotype. Results. There were significant main effects for stressful life events but there was no evidence for any effect of 5-HTT genotype, nor a genotype × stressful life event interaction. Conclusions. Regardless of whether our results were based on binary logistic or ordinal regression analyses we found no evidence to support a main effect of 5-HTTLPR, or an interaction between the 5-HTTLPR genotype and stressful life events on major depression. Only 20% of our subjects were aged below 30 years. It is possible that the effect reported by Caspi and colleagues is specific to young people, in which case our study has much less power in this age group.