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Background: As part of the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted mass drug administration (MDA) from 2000–2006, and passed transmission assessment surveys in 2011–2012. We examined the seroprevalence and spatial epidemiology of LF post-MDA to inform strategies for ongoing surveillance and to reduce resurgence risk. Methods: ELISA for LF antigen (Og4C3) and antibodies (Wb123, Bm14) were performed on a geo-referenced serum bank of 807 adults collected in 2010. Risk factors assessed for association with sero-positivity included age, sex, years lived in American Samoa, and occupation. Geographic clustering of serological indicators was investigated to identify spatial dependence and household-level clustering. Results: Og4C3 antigen of >128 units (positive) were found in 0.75% (95% CI 0.3–1.6%) of participants, and >32 units (equivocal plus positive) in 3.2% (95% CI 0.6–4.7%). Seroprevalence of Wb123 and Bm14 antibodies were 8.1% (95% CI 6.3–10.2%) and 17.9% (95% CI 15.3–20.7%) respectively. Antigen-positive individuals were identified in all ages, and antibody prevalence higher in older ages. Prevalence was higher in males, and inversely associated with years lived in American Samoa. Spatial distribution of individuals varied significantly with positive and equivocal levels of Og4C3 antigen, but not with antibodies. Using Og4C3 cutoff points of >128 units and >32 units, average cluster sizes were 1,242 m and 1,498 m, and geographical proximity of households explained 85% and 62% of the spatial variation respectively. Conclusions: High-risk populations for LF in American Samoa include adult males and recent migrants. We identified locations and estimated the size of possible residual foci of antigen-positive adults, demonstrating the value of spatial analysis in post-MDA surveillance. Strategies to monitor cluster residents and high-risk groups are needed to reduce resurgence risk. Further research is required to quantify factors contributing to LF transmission at the last stages of elimination to ensure that programme achievements are sustained. Author Summary: Lymphatic filariasis (LF) is caused by infection with filarial worms that are transmitted by mosquito bites. Globally, 120 million people are affected, and 40 million are disfigured and disabled by complications such as severe swelling of the legs (elephantiasis). The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through mass drug administration (MDA), and to control illness and suffering in affected persons. In American Samoa, significant progress has been made towards LF elimination, and antigen prevalence has dropped from 16.5% in 1999 to <1% in 2011/2012 after seven rounds of MDA. Current challenges include identification of any residual hotspots of ongoing transmission, and effective strategies for early identification of any resurgence. Our study examined the prevalence and spatial distribution of LF antigens and antibodies in American Samoan adults to improve understanding of LF transmission in an area of low prevalence, develop tools and strategies to more accurately verify interruption of transmission, and provide evidence-based guidance for future elimination strategies in American Samoa. [ABSTRACT FROM AUTHOR]