It really depends.
With two instances on the same web server you will have to handle all sorts of redirect rules, etc at the server level. Also I would think this becomes tricky with proper load balancing. Not to mention the increase in maintenance in updating the core files twice. Multisite also lets you manage plugins, etc from one place across all products.
I have seen installs with 56 different sites on one multisite install and all the sites ran like a charm. Some were blogs, news sites, photo sharing sites, ecommerce, etc all on one multisite and they all ran very well at near 2 million users.
Now the downside of multisite is one point of failure. If there is some really nasty plugin that fails then all sites can suffer.
My experience tends towards easier management with multisite although if one is truly alot different than the other install two is not necessarily bad. For example if the "new" site is being built for a client or you plan to sell it. Lets say I had a personal blog and then created the next "tweeter" service. If I plan on selling it I would probably do two installs. That way I can simply hand over the code, db, and credentials and theres no need to figure out how to take my personal blog with me.
As far as getting a bit off topic at the end of the day some of this comes down to your setup, configuration, and hardware.