Clinical symptoms of syphilis are the consequence of the spirochete propensity to induce persistent chronic inflammation, which could participate to oxidative stress increase. The present study was designed to evaluate the level of oxidative stress biomarkers and antioxidant defences in a cohort of syphilitic patients. Serum oxidative status was explored in 63 patients diagnosed with early syphilis, 34 consulting patients negative for syphilis and 19 healthy controls. Total plasma thioredoxin (Trx) and thiols were determined as antioxidant capacity markers, °NO, advanced oxidation protein products (AOPP) and protein carbonyl levels as oxidative stress status biomarkers, and CRP as marker of inflammation. Mean serum levels of Trx, AOPP, carbonyls, and nitrates/nitrites were significantly higher, whereas thiols level was lower in syphilitic patients compared to non-syphilitic patients and healthy controls (respectively, p < 0.05/p < 0.01 for Trx, p < 0.005/p < 0.0001 for AOPP, p < 0.05/p < 0.005 for carbonyls, p < 0.005/p < 0.05 for nitrates/nitrites and p < 0.01/p < 0.0001 for thiols). According to the stage of the disease, results highlighted a marked and sustained oxidative stress imbalance from the first stage to the latent period of the disease. Moreover, syphilitic patients presented a low inflammation status reflected by median of CRP level (1.7 mg/L, range 5th-95th percentile from <0.1 to 33.7 mg/L), correlated with antioxidant capacity decrease (thiols) at stage 1 (r = -0.725; p < 0.0001) and nitrosative stress increase (nitrates/nitrites) at stage 2 and latent (respectively, r = 0.285, p < 0.05 and r = 0.650, p < 0.05). These findings indicate that at all stages of the disease, despite a low-grade inflammatory state, syphilis infection generates a major oxidative and nitrosative stress which may be involved in the pathophysiology of the disease.