We hold that the intra-blood-brain-barrier (BBB) IgG synthesis (SYN) rate can be quantitated reliably and validly. Although several formulas distinguish patients with multiple sclerosis from normal controls equally well, only the SYN rate formula has been validated in humans using isotopic tracer techniques. Our formula for the IgG SYN rate is reducible to Reiber's formula; therefore, both can be used to quantify the IgG SYN rate in a manner not possible using the IgG index. Although our SYN rate formula has been validated for a modest range of BBB abnormalities (cerebrospinal fluid/serum albumin ratios), there is evidence to suggest that it may be used even in patients having severe BBB damage. We question the acceptance of unique cerebrospinal fluid IgG bands as indisputable evidence of intra-BBB IgG SYN in the presence of a modest to severely damaged BBB. Finally, the utility of quantitation and detection of intra-BBB IgG SYN by standardized methods in a group of asymptomatic, normal individuals compared with a group of patients with clinical definite multiple sclerosis is presented.