Onchocerciasis remains a major health hazard in many tropical countries. However, the existing tools for diagnosis of the disease have limitations, particularly regarding the detection of low level or early infections. To design an optimized reagent, we exploited the high antibody reactivity of patient sera against the Onchocerca volvulus proteins Ov20 and Ov33, which have been described as highly sensitive and specific immunodiagnostic reagents for producing hybrid proteins. The construct OvH2 was composed of Ov20 fused to Ov33, while OvH3 consisted of the C-terminus of Ov20 linked to Ov33. When these constructs were tested with sera from patients with onchocerciasis and control sera, OvH2 showed a sensitivity of 98.5% and a specificity of 97.7% and OvH3 showed a sensitivity of 98.5% and a specificity of 95.35%. All non-responders were from Ecuador. These results surpass those of existing single recombinant antigens, suggesting that our hybrid proteins combined the sensitivity of the two parent proteins. Tests based on OvH2 should prove suitable for monitoring onchocerciasis control programs and individual diagnosis.