Mixed sizes of scaled-up pixels bug me, especially pixels not at power-of-2 scalings to each other, but I think the contrast between obviously scaled-up pixel graphics and native resolution antialiased graphics can sometimes be useful, e.g. smooth for text and UI elements, pixel for the actual game graphics.
I guess as with many things the rule is: try it and see what works. That or I'm just a pixel philistine.
Never thought about that before, but I completely agree!