One large VMDK file or smaller ones

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Now with esxi 5.5, we can have 64 TB vmdk files, but is there a performance benefit of having multiple vmdk's in multiple datastores, or just having one large vmdk?  I could see the benefit for a large number of vmdk's and VM's, but if it's just for backup purposes using MS DPM, is there any reason I should consider one over the other?  Thanks.
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Commented:
If you have the luxury of tiered storage, and different SANs/Volumes/LUNs, offering SAS, SATA and SSD, different RAID types using multiple datastores, then having different VMDKs on different datastore technologies you will see a performance benefit, because of the differing datastore characteristics.

If these are single VMDKs, but are you referring to have multiple 2TB VMDKs to make up a 64TB VMDK spanned internally in the OS?

For simplicity I would use a single large VMDK if you need a super sized virtual disk for your VM.

BUT, we use multiple disks, and datastores for resilience, just in case a LUN or store gets corrupted.

A supersize LUN/datastore or virtual disk, all your eggs in one basket!

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