It is well known that depth-of-focus (DOF) is influenced by optical factors (such as pupil size and monochromatic aberrations). However, neural factors such as blur sensitivity and defocus adaptation may play an important role on the extent of DOF. A series of experiments were conducted to study if optical or neural factors are most pertinent in explaining the variability of DOF across subjects. An adaptive optics system with a black and white target, a 3.8-mm artificial pupil, and a subjective criterion (based on objectionable blur) were used to measure depth of field ([DOFi]; DOF computed in the object space) in 11 participants, after at least 6 min of adaptation. This was done under three conditions: (a) with their own higher order aberrations (HOA); (b) after correction of their monochromatic HOA; and (c) after altering the HOA pattern for some participants to reflect the HOA pattern measured for a different participant. Natural DOFi and DOFi after HOA correction were positively correlated (R2 = 0.461), but a significant decrease in DOFi (21% on average) was found after HOA correction (p = 0.042). Effect of HOA on the intersubject variability of DOFi was 3.9 times smaller than the effect of the image neural processing. This study shows that DOFi depends on both optical and neural factors, but the latter seems to play a more important role than the former.