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Objective Mass drug Administration (MDA) for the control of Lymphatic filariasis (LF), in Ghana, started in the year 2000. While this had great success in many implementation units, there remain areas with persistent transmission, after more than 10 years of treatment. A closer examination of the parasite populations could help understand the reasons for persistent infections, and formulatingn appropriate strategies to control LF in these areas of persistent transmission. Materials and Methods In a longitudinal study, we assessed the prevalence of microfilaraemia (mf) in two communities with 12 years of MDA in Ghana. In baseline surveys 6 months after the National MDA in 2014, 370 consenting individuals were tested for antigenaemia using immunochromatographic test (ICT) cards, and had their mf count determined through night blood surveys. 48 ICT positives, of whom 17 were positive for mf, were treated with 400 μg/kg ivermectin + 400 mg albendazole and subsequently followed for parasitological assessment at 3-month intervals for 1 year. This overlapped with the National MDA in 2015. Results There was a 68% parasite clearance 3 months after treatment. The pre-treatment mf count differed significantly from the post-treatment mf counts at 3 months (p = 0.0023), 6 months (p = 0.0051), 9 months (p = 0.0113) and 12 months (p = 0.0008). Conclusion In these settings with persistent LF transmission, twice-yearly treatment may help accelerate LF elimination. Further large-scale evaluations are required to ascertain these findings. This article is protected by copyright. All rights reserved.