I need to build a rectangular plywood box. The dimensions will be something like 12"x12"x48". One of the ends needs to be capped, but I could cap both ends. I was thinking about running 2x4's along the inside vertically and just nailing the plywood to them. I would then run small blocking perpendicular to the studs. This seems like a little overkill though. It will be used to support about 25 lbs.
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Your described use of 2x4s would work of course but that's not joinery, it's butchery. What kind of tools / skills do you have? How thick is the plywood? If it's thin, you may HAVE to resort to something like what you mention, but for thicker plywood there are lots of joints that would work well.
To get the 12" finished dimension make a 1/4" rabbet on 2 sides of the box , then use 11 1/2 sides for the opposite ones. Rabbet the top and botom in and it will be strong. bill
The best advice is from someone who has actually done the operation, owns the same or similar tool or machine and who has experience with the material. BTDT? But that advice is "free", so take your chances ... you get what you pay for.