Realistic estimates of the longterm risk of PML are almost double the published figures.

The risk with a JCV index of 1.1 and no prior IS use is 9 times higher than previously thought.

Current risk-stratification remains a gamble even with the proper inclusion of the JCV index.

The 0.9 JCV index cutoff promoted as a means of avoiding most PML cases is too optimistic.

We present statistically significant evidence that JCV serology testing has been valuable.