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Background: Rhesus-positive and rhesus-negative persons differ in the presence-absence of highly immunogenic RhD protein on the erythrocyte membrane. This protein is a component of NH3 or CO2 pump whose physiological role is unknown. Several recent studies have shown that RhD positivity protects against effects of latent toxoplasmosis on motor performance and personality. It is not known, however, whether the RhD phenotype modifies exclusively the response of the body to toxoplasmosis or whether it also influences effects of other factors. Methodology/Principal Findings: In the present cohort study, we searched for the effects of age and smoking on performance, intelligence, personality and self-estimated health and wellness in about 3800 draftees. We found that the positive effect of age on performance and intelligence was stronger in RhD-positive soldiers, while the negative effect of smoking on performance and intelligence was of similar size regardless of the RhD phenotype. The effect of age on four Cattell's personality factors, i.e., dominance (E), radicalism (Q(1)), self-sentiment integration (Q(3)), and ergic tension (Q(4)), and on Cloninger's factor reward dependency (RD) was stronger for RhD-negative than RhD-positive subjects, while the effect of smoking on the number of viral and bacterial diseases was about three times stronger for RhD-negative than RhD-positive subjects. Conclusions: RhD phenotype modulates the influence not only of latent toxoplasmosis, but also of at least two other potentially detrimental factors, age and smoking, on human behavior and physiology. The negative effect of smoking on health (estimated on the basis of the self-rated number of common viral and bacterial diseases in the past year) was much stronger in RhD-negative than RhD-positive subjects. It is critically needed to confirm the differences in health response to smoking between RhD-positive and RhD-negative subjects by objective medical examination in future studies.