I do believe that this is the “eternal mousegun debate”, that is if you’ve decided to carry a popgun that starts with a “2”, which should you choose, the .22 LR or the .25 ACP? You’ll sometimes here people saying that the .22 LR produces superior ballistics to the .25 ACP, so you should carry that. That statement is only partially true.
The .22 LR does produce superior ballistics to the .25 ACP, when you fire the .22 out of a pistol with a four inch barrel. From a 2-3 inch barrel like you’ll find on most teeny mouseguns, the .22 LR actually produces very similar ballistics to the .25 ACP. If you look at this article on the topic of .22 vs. .25 and compare the ballistics from the Baby Browning to those of the .22 mini revolver, you’ll see that they’re remarkably the same.
This article from the Firearms Tactical Institute tests various .22 LR ammo in ballistics gel for penetration. I’m not asking you to agree with their conclusions, but their data is interesting. The only .22 LR round that “outperforms” the .25 in terms of muzzle velocity is the CCI Stinger, which should be noted still failed to expand at those muzzle velocities. You can decide if that’s a good thing or a bad thing.
The most important factor in a defensive pistol is its ability to go “bang” every time you press the trigger. The reliability factor does create something of a problem for the .22 LR mouseguns; the rimmed cartridge and the occasional lack of attention to detail that is sometimes paid to .22 ammo are big strikes against carrying it in your teeny defensive gun. Additionally, the rimfire ignition system is less reliable than a centerfire ignition system; the .25 ACP is a centerfire cartridge. On the issue of reliability, the .25 ACP wins easily.
Personally, if I were to carry a small semi-automatic pistol for self defense, I would probably go with a .25 ACP. Although (in the past) I’ve carried a Walther P22, a few recent issues with CCI Stingers being poorly loaded or having other ammo related failures have caused me to retire the P22 to “fun gun only”. For the P22 haters, don’t take that to mean that I don’t love my P22 any more, because the issues were strictly ammo related. However, when a “quality” round like a CCI Stinger is having issues, it made me question the logic behind carrying a .22 LR.
When it gets down to it, the debate about which is a better manstopper is no debate at all. They’re about the same, and both calibers are going to make little dinky holes in an assailant. For me, the deciding factor would have to be reliability, and that would make me pick a .25 ACP.