With external power and an external antenna, it should work just fine.
Will it work well? Hard to say. Big issue I've always seen is that the portable radios have smaller speakers and are harder to hear at highway speeds. Also, having it sitting in your center console with coaxial cable and power cables gets to be an annoyance in my opinion.
There are some mighty small CB's out there now, have you looked at any of them?
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I very, very rarely use CB, but when I was doing a long trip a few years back, I purchased the CMX560, same radio as above without weather channels and a few other functions. The RF deck portion is about the size of a small paperback book. All the controls are in the hand held control head. The cable between the control head and hand held part is just 4 pair cable and I was easily able to extend it with an Ethernet patch cord. I mounted the RF deck behind my rear seat with my other radios, and just had the control head up front. I added an external speaker to help since the small speaker in the mic can be a bit hard to hear.
Benefit to that type of install is that it's always there, it's hidden well, you can disconnect the mic when you are not using, it can be permanently wired and tucked up out of the way under the dash, under a seat, etc.