Abstract Tick blood feeding is facilitated by numerous secreted tick salivary molecules. Some are important for forming and maintaining a feeding cavity in the host skin while others modulate pain or are immunosuppressive. Tick salivary gland genes also express proteins that bind host macromolecules, like histamine and IgG. In addition to these tick-derived proteins, tick saliva also contains high concentrations of certain host proteins. Some of these host proteins, including albumin, IgG and transferin, were highly reactive to Ixodes scapularis-sensitized host sera in Western blots. We investigated the mechanism by which tick infested hosts might become immune to one of these ‘self’ proteins, albumin. Albumin was purified from nymphal and adult I. scapularis blood fed on rabbits, guinea pigs and mice. Western blots using sera from tick-sensitized and non tick-sensitized (naïve) hosts showed that naïve sera gave no reaction to the purified albumin while reactivity of the tick-sensitized sera was host specific. MALDI-TOF analysis of the purified albumin suggested that it was a single protein (lacking tick derived binding protein). Additionally, the albumin was neither N- or O-glycosolated. Collectively, the data suggest a structural modification, which occurs in the tick midgut, may be responsible for making host albumin immunogenic. The abundant tick recycled host proteins may manipulate the host immune response in order to ‘protect’ important tick-derived molecules used to facilitate blood feeding. The role of tick-recycled host proteins as a possible stimulator of auto-immunity is being investigated.