I've had very good luck with using AuthImage http://www.gudlyf.com/index.php?p=376 to prevent comment spam. It's a captcha, which means that there's an extra step for people leaving comments, but it's a pretty easy step and it's worked perfectly, 100% of the time.
However, I recently ran into a first-time problem with trackback spam. I turned off trackbacks completely, which took care of that, but maybe I should give spam-karma a try if it works to prevent trackback spam, too.