PURPOSE: To explore the effect of docosahexaenoic acid (DHA) on gene expression during human fetal retinal maturation. METHODS: Human fetal retinal explants were cultured in serum-free Waymouth's medium supplemented with DHA or oleic acid (OA), using bovine serum albumin (BSA) as the vehicle. After 14 days in culture, fatty acid composition was assessed, and the abundance of 2400 cDNAs was examined with a human cDNA microarray system. RESULTS: Transcript abundance remained unchanged for 82% and 90% of genes in the explants with added DHA or OA, respectively. Decreased expression was detected in 4% and 9% of genes, in explants supplemented with DHA or OA, respectively, whereas, 14% of genes in explants exposed to DHA and only 0.4% of genes in explants treated with OA showed increased expression. Transcripts displaying changes in abundance in explants supplemented with DHA encode for proteins involved in diverse biological functions, including neurogenesis, neurotransmission, and refinement of connectivity. These gene expression changes were not observed in explants supplemented with OA. CONCLUSIONS: The effect of DHA deficiency on retinal function during human development can be partly explained by modifications in retinal gene expression by direct or indirect mechanisms.