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Many vectors acquire or transmit pathogens through the process of blood feeding. Here, we report adiponectin, the most abundant adipocyte-derived hormone circulating in human blood, directly or indirectly inhibits acquisition of the Lyme disease agent, <jats:italic>Borrelia burgdorferi<\/jats:italic>, by <jats:italic>Ixodes scapularis<\/jats:italic> ticks. Rather than altering tick feeding or spirochete viability, adiponectin or its associated factors induces host histamine release when the tick feeds, which leads to vascular leakage, infiltration of neutrophils and macrophages, and inflammation at the bite site. Consistent with this, adiponectin-deficient mice have diminished pro-inflammatory responses, including interleukin (IL)-12 and IL-1\u03b2, following a tick bite, compared with wild-type animals. All these factors mediated by adiponectin or associated factors influence <jats:italic>B<\/jats:italic>. <jats:italic>burgdorferi<\/jats:italic> survival at the tick bite site. 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