It is not fully understood how the fraction of exhaled nitric oxide (FeNO) varies with age and gender in healthy individuals. We aim to describe the evolution of FeNO with age, giving special regard to the effect of gender, and to relate this evolution to natural changes in the respiratory tract.We studied 3081 subjects from NHANES 2007-08 and 2009-10, aged 6-80 years, with no self-reported diagnosis of asthma, chronic bronchitis or emphysema, and with normal values of blood eosinophils and C-reactive protein. The relationship of the mean values of FeNO to age, in all participants and divided by gender, was computed, and compared with changes in anatomic dead space volume and forced vital capacity. A change-point analysis technique and subsequent piecewise regression was used to detect breakpoints in the evolution of FeNO with age.Three distinct phases in the evolution of FeNO throughout the age range 6-80 years can be seen. FeNO values increase linearly between 6-14 years of age in girls and between 6-16 years of age in boys, in parallel with somatic growth. After that, FeNO levels plateau in both genders until age 45 years in females and age 59 years in males, when they start to increase linearly again. This increase continues until age 80.Our data clearly show a triphasic evolution of FeNO throughout the human age range in healthy individuals. This should be accounted for in development of reference equations for normal FeNO values.