Our study group consisted of 54 elderly patients without major invalidating diseases who were randomly divided into two fully matched groups. Group A was given a certified fermented papaya preparation 9 g/day by mouth, while group B received placebo. Treatment was carried out in a cross-over manner with a 3-month supplementation followed by a 6-week washout period. Blood samples were drawn at entry and on a monthly basis to check routine parameters, redox status, and 8-OHdG in circulating leukocyte DNA. Polymorphism analysis of GSTM1 was carried out as well. The glutathune-S transferase M1 (GSTM1) genotype was null (−) in 40% and 46% of groups A and B, respectively. GSTM1 (−) smokers had a significantly higher level of plasma DNA adducts and leukocytes level of 8-OHdG than their GSTM1 (+) counterparts (P < 0.01). There was a weak correlation between cigarettes smoked/day and DNA adduct (r: 0.61, P < 0.05), which also correlated with antioxidant concentrations, but only in GSTM1 (−) smokers (P < 0.01). The fermented papaya preparation (FPP)–supplemented group showed a significant enhancement of the antioxidant protection (P < 0.01 vs. A) within the subgroups with GSTM1 (−) and of plasma DNA adduct, irrespective of the GSTM1 genotype. Only the GSTM1 (−) subgroup was the one that, under FPP treatment, increased lymphocyte 8-OHdG (P < 0.01). Such preliminary data show that FPP is a promising nutraceutical for improving antioxidant-defense in elderly patients even without any overt antioxidant-deficiency state while helping explain some inconsistent results of prior interventional studies.