The management of cystic echinococcosis (CE) is still problematic, since the post-surgical period is marked by high rates of relapses that, often, could not be early detectable with the available imaging methods. The aim of our study was the search of reliable serological biomarkers for the early prediction of CE post-operative outcomes. Here, we applied an innovative proteomic approach based on immunoprecipitation (IP) of Echinococcus granulosus (E. granulosus) protoscolex antigens with plasma collected at 1-month and 1-year post-surgery, from pediatric CE-confirmed patients, followed by LC-MS/MS. We compared IP proteomic content from patients relapsed within the first-year post-surgery (RCE) to cases with no detectable relapses until 3 post-operative years (NRCE) and selected the most promising candidates. These proteins were produced under recombinant form and assessed for their prognostic performance by ELISA. A total of 305 immunoreactive parasitic proteins were identified, 59 of which, were significantly more abundant in RCE than NRCE for both time-points. We selected four proteins derived from E. granulosus protoscolex as promising prognostic biomarkers for predicting CE post-surgical outcomes: cytoplasmic malate dehydrogenase (Eg-cMDH), citrate synthase (Eg-CS), Annexin A6 (Eg-ANX A6) and severin (Eg-SVN). ELISA results showed that IgG antibodies against the four markers were significantly lower at 1-year post-surgery than 1-month in NRCE, in contrast to RCE group that displayed either a stable or higher IgG levels. The Eg-cMDH and Eg-CS showed the best prognostic performance with respective probabilities of being “relapse-free” of 83% and 81% if a decrease of IgG levels occurred between 1-month and 1-year post-surgery.