I know there are a couple of key characteristics that determine the reliability of HDDs, but is there a difference between 2.5" and 3.5" drives?
In the past I've always assumed that 3.5" drives were likely to be more robust...but I am now questioning that because I have absolutely no evidence (let alone a half-baked theory) to back it up.
No not really, 2.5 and 3.5 inch drives are mostly the same, including interface and whatnot but 3.5 inch drives are usually faster and larger in space because there is more stuff you can fit into 2.5 vs 3.5 inches. 3.5s are cheaper because of space constrains but usually no more reliable than a 2.5 and vise versa. (in practice)If you could fit a 3.5 drive do it, it'll be cheaper and bigger(storage wise)
You can't base that just on the form-factor. What's way more important is how the vendor dedicates the hard disk. There are consumer disks with both sizes, which are mainly meant for running just a few hours a day and are lightly loaded.
Enterprise disks (SAS, nearline-SATA) are dedicated for 24/7 usage and higher loads. So if you need reliability, use those.
The most important characteristic to consider when choosing between 3.5" and 2.5" is typically size and energy consumption. If you are tight on both, you should choose 2.5", else you could go with 3.5" which are typically cheaper per GB.
The real question is what are you you trying to do? If you have a choice between two enclosures, check with the vendor(s) to see what disks are being put in, and see what the warranty period and the manufacturers MTBF on the drives.
Personally, I have seen 2.5" drives fail on me more frequently than 3.5" drives, and I have seen 2.5" drives have 1-3 year warranties versus 3-5 year warranties for 3.5" drives. To be sure, 2.5" drives are more likely to be installed in laptops, which tend to bounce around and have less ventilation.
Coming from someone who works on computers regularly I would say in my opinion 2.5" drives are crap. They most generally cost more for the same GB and in my experience fail at, at least 3x the rate of the 3.5" drives. Just as an example I have a WD Blue 2.5" not even 1 year old that was never even installed in a laptop and has been sitting in my desktop since day 1. It is now a paper weight. In my same desktop I have a WD 3.5" drive that was made like 4 to 5 years ago, has been moved around from one desktop to another I don't know how many times and it works just as good as the day I got it. The sad part is I don't even like WD but I got a good deal on that Blue drive and was under the impression they are supposed to be reliable. I usually go with Seagate as I have about 10 of their various SATA1 to SATA3 3.5" drives that do nothing all day but serve media files and get accessed constantly while uploading torrents. Just my 2 cents.