We have a couple of large stores (10,000 + products) and I generally run Easypopulate updates in "tranches" - by manually splitting the tab-delimited files to more manageable numbers.

In our big store (15,650 products) I generally split the main spreadsheet into three section (roughly 5,000 products each), then run each of these through EP.

It takes a bit longer - but it generally avoids errors.

... and I ALWAYS do the EP from the temp folder in the site itself - never via a remote upload.