The ability to diagnose Loa loa infection readily and accurately remains a demanding task. Among the available diagnostic methods, many are impractical for point-of-care field testing. To investigate whether luciferase immunoprecipitation systems (LIPS) can be used for rapid and specific diagnosis of L. loa infection, a LIPS assay was developed based on immunoglobulin G (IgG) and IgG4 subclass antibodies to a recombinant L. loa SXP-1 (designated LlSXP-1) antigen and tested with sera from healthy controls or patients with proven infection with L. loa, Mansonella perstans, Onchocerca volvulus, Strongyloides stercoralis, or Wuchereria bancrofti. A LIPS test measuring IgG antibody against LlSXP-1 readily differentiated L. loa-infected from uninfected patients and demonstrated markedly improved sensitivity and specificity compared with an LlSXP-1 IgG4-based enzyme-linked immunosorbent assay (67% sensitivity and 99% specificity). No significant immunoreactivity was observed with S. stercoralisinfected sera, but a small number of patients infected with O. volvulus, M. perstans, or W. bancrofti showed positive immunoreactivity. Measuring anti-IgG4-specific antibodies to LlSXP-1 showed a significant correlation (r ϳ 0.85; P < 0.00001) with the anti-IgG results but showed no advantage over measuring the total IgG response alone. In contrast, a rapid LIPS format (called QLIPS) in which the tests are performed in less than 15 minutes under nonequilibrium conditions significantly improved the specificity for cross-reactive O. volvulus patient sera (100% sensitivity and 100% specificity). These results suggest that LIPS (and the even more rapid test QLIPS) represents a major advance in the ability to diagnose L. loa infection and may have future applications for point-of-care diagnostics.The development of rapid diagnostic assays for onchocerciasis (22) and lymphatic filariasis (20) has not only simplified the care of individual patients with these filarial infections but also allowed accurate and cost-effective geographic mapping for the purpose of mass chemotherapy in areas of endemicity (21) and for use in the certification process of elimination (15). Nevertheless, the coendemicity of loiasis with these and other filarial infections of humans remains an issue because of species-specific differences in the responses to available antifilarial therapies. This has been of particular concern in the setting of both the African Program for Onchocerciasis Control (APOC) and the Global Program for the Elimination of Lymphatic Filariasis (GPELF), where mass drug administration has ground to a halt in certain areas of Africa because of deaths related to ivermectin administered as part of mass treatment programs for onchocerciasis control (3,12).Although the definitive diagnosis of Loa loa infection can be made morphologically by identifying microfilariae in the blood or, rarely, after surgical removal of the adult worm (typically from its subconjunctival location), a proportion of infected individuals are amicrofilaremic (9, 13). PC...