ObjectiveThe low level of passively diffused IgG through the blood–brain barrier is sufficient to blur the estimation of intrathecal IgG synthesis (ITS). Therefore, this estimation requires a mathematical calculation derived from empirical laws, but the range of normal values in healthy controls is wide enough to prevent a precise calculation. This study investigated the precision of various methods of ITS estimations and their application to two clinical situations: plasma exchange and immune suppression targeting ITS.MethodsBased on a mathematical model of ITS, we constructed a population of healthy controls and applied a tunable ITS.ResultsWe demonstrate the following results: underestimation of ITS is common at individual level but true ITS is well fitted by cohorts; Q IgG increases after plasma exchange; IgG Loc calculation based on Qlim falsely increases when Q Alb decreases; the sample size required to demonstrate a decrease in ITS increases exponentially with larger Q Alb.InterpretationStudies evaluating changes in ITS level should be adjusted to Q Alb. Low amounts of ITS could be largely underestimated.