Have you turned off autorecalculation? If you have vast numbers of lookups for example it will do them all every time you open it.
When you do recalculate manually, IIRC shift+F9 recalculates the active sheet only, not the entire workbook - can be risky but saves some processing.
That said, I have had this sort of problem with Excel - it feels like a bug to me, once in a while I seem to do something that just won't work properly, even when I check and check again, and I end up working round it.
Have you got any 'solve' operations going on?
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Open Office Beats Excel with Excel File new
Open Office Beats Excel with Excel File new
