Background: In endemic areas, children develop slowly and naturally develop anti-Plasmodium antibodies and become semi-immune. Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine + amodiaquine (SPAQ) is a new strategy to reduce malaria morbidity in young children in West Africa. However, SMC may impact on the natural acquisition of anti-Plasmodium immunity. We evaluated the effect of SMC with SPAQ on malaria antibody concentration in Niger.Methods: This survey was conducted in areas targeted with SMC since 2014 (Zinder district), without SMC (Dosso district), and with one year SMC 2016 (Gaya district). To assess the relationship between SMC and P. falciparum IgG antibody responses, we compared total antibody concentrations against two P. falciparum asexual stage vaccine candidate antigens, circumsporozoite protein (CSP) and glutamate-rich protein R2 (GLURP-R2), in children aged 3-59 months across the three sites. Antibody concentrations were quantified using an enzyme-linked immunosorbent assay (ELISA) on the elution extracted from positive and negative RDT cassettes.Results: A total of 229 children aged 3-59 months were included in the analysis: 71 in Zinder, 77 in Dosso, and 81 in Gaya. In Zinder (CSP=17.5µg/ml and GLURP-R2=14.3µg/ml) median antibody concentration observed were higher than in Gaya (CSP=7.7 µg/ml and GLURP-R2=6.5 µg/ml) and Dosso (CSP=4.5 µg/ml and GLURP-R2=3.6 µg/ml) (p<0.0001). Conclusion: We have some evidence that seasonal malaria chemoprevention with SPAQ has an effect on blood stage antibody responses and pre-erythrocytic stage of Plasmodium falciparum infections in Niger. Future studies are necessary to provide better understanding of the effect of on malaria immunity.