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Background Zika, dengue and chikungunya viruses (ZIKV, CHIKV and DENV) are temporally associated with neurological diseases, such as Guillain-Barré syndrome (GBS). Because these three arboviruses coexist in Mexico, the frequency and severity of GBS could theoretically increase. This study aims to determine the association between these arboviruses and GBS in a Mexican population and to establish the clinical characteristics of the patients, including the severity of the infection. A case-control study was conducted (2016/07/01-2018/06/30) in Instituto Mexicano del Seguro Social (Mexican Social Security Institute) hospitals, using serum and urine samples that were collected to determine exposure to ZIKV, DENV, CHIKV by RT-qPCR and serology (IgM). For the categorical variables analysis, Pearson’s χ2 or Fisher exact tests were used, and the Mann-Whitney U test for continuous variables. To determine the association of GBS and viral infection diagnosis through laboratory and symptomatology before admission, we calculated the odds ratio (OR) and 95% confidence intervals (95%CI) using a 2x2 contingency table. A p-value ≤ 0.05 was considered as significant. Ninety-seven GBS cases and 184 controls were included. The association of GBS with ZIKV acute infection (OR, 8.04; 95% CI, 0.89–73.01, p = 0.047), as well as laboratory evidence of ZIKV infection (OR, 16.45; 95% CI, 2.03–133.56; p = 0.001) or Flavivirus (ZIKV and DENV) infection (OR, 6.35; 95% CI, 1.99–20.28; p = 0.001) was observed. Cases of GBS associated with ZIKV demonstrated a greater impairment of functional status and a higher percentage of mechanical ventilation. According to laboratory results, an association between ZIKV or ZIKV and DENV infection in patients with GBS was found. Cases of GBS associated with ZIKV exhibited a more severe clinical picture. Cases with co-infection were not found., Author summary Dengue (DENV), chikungunya (CHIKV), and Zika (ZIKV) are considered as emerging or re-emerging viruses. Recently, these viruses have produced major epidemics in tropical climate urban centers, and have been associated with neurological manifestations, including Guillain-Barre syndrome (GBS), which causes muscle weakness, unstable gait, and decreased or absent musculoskeletal reflexes. This study aims to investigate the association between these viral infections and GBS. A case and control study was conducted nationwide, including 97 cases of GBS and 184 controls matched by age, gender, and locality, but not the disease. The study shows a positive association between GBS cases and ZIKV or ZIKV and DENV infection. GBS cases associated with ZIKV depicted a more severe clinical picture (more impairment of functional status, incapacity, and a higher percentage of mechanical ventilation). Finally, the symptoms of suspected ZIKV disease prior to the development of GBS were similar to some previous reports. The impact of the interaction of these three arboviruses, particularly ZIKV, on the health of the Mexican population was less than expected. The Mexican experience could be useful for other populations.