I think it all depends on the game you intend to safety save on.
For example, some games can be about roleplay for a while, but the vast plethora of obtainable things becomes overwhelming, and a kleptomaniac-obsessive-compulsive such as myself eventually folds to the desire to have accomplished as much as I can in one save, to stop myself playing through the game an absurd amount of times to see it all. I have never found Bethesda games very immersive, they always seem to hammer you in to one type of play or another, never really letting your forge your own path. After so many playthroughs, player fuck-up is going to lead to you not getting something that you started the playthrough exclusively for.
In short, for roleplay and character immersion, save only before combat or the end of play. For maximum attainment, safety save to your hearts content. Your character may become a disconnected husk, but said disconnected husk will have a ton of awesome crap to shoot people with.
(Or look at, in my case. -.-)