Objective In earlier analyses of nonHispanic White women we found a stronger relation between abuse history and midpregnancy elevated depressive symptoms in women with the serotonin transporter (5-HTTLPR) S/S genotype. Here, we focus on African-American women (N= 698). Our inquiry is motivated by racial differences in depression diagnosis/treatment, stressors, and frequency of major 5-HTTLPR alleles (S, L(A), L(G)). Materials and methods Stressful life events (lifetime) and depressive symptoms (current) were ascertained at 15-27 weeks gestation. A Center for Epidemiological Studies Depression Score of more than or equal to 18 was considered 'elevated'. Life events were scored together and separated into six subconstructs. 5-HTTLPR genotypes were grouped as follows: (i) L and S alleles, (ii) S-LG equivalence ('triallelic to biallelic'), and (iii) LA/LA, all others, S/S ('high/intermediate/low'). Odds ratios (OR) for 'elevated' depressive symptoms-life events (total and subconstructs) relations were calculated for each genotype grouping. Results The prevalence of 'elevated' depressive symptoms did not vary by genotype. The relation between stressful life events and 'elevated' depressive symptoms was stronger in S/S compared with LA/LA genotype (interaction P = 0.11). Of the six subconstructs, only abuse showed a statistically significant gene-environment interaction. The OR for the abuse-'elevated' depressive symptoms association was greater for S/S vs. LA/LA genotype (interaction P = 0.03) and in the 'triallelic to biallelic' grouping (interaction P = 0.04). In the 'high/intermediate/low' grouping, 'low' (S/S) had a higher OR (5.5) than both 'intermediate' and 'high' (ORs <= 2.3) (interaction P = 0.10). Conclusions These results show the importance of examining racial groups, specific stressful events, and different 5-HTTLPR genotype groupings when exploring gene-environment interactions in depression. Psychiatr Genet 21: 271-280 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Psychiatric Genetics 2011, 21: 271-280