The techno geeks are going to tell you that electronically controlled fuel injection and ignition is going to be the most reliable and give you the best fuel economy. I run pre 88 350's with Q-jets and mechanically advanced HEI's and get great fuel economy and longevity. The last motor I built and tuned had over 500,000 miles on it before it died(blew)in a mud truck.
The one that will be going in my 91 1/2 ton only has 10,000 on it and gets 19mpg in a 3500 pound car. I'm hoping for 17 in the truck with the overdrive tranny.
Don't expect to pull a carb or distributor out of the box,bolt it on and have it perform. You have to tune them to make them work for your application. Not any different than tuning a CC system except you will have do some actual work and maybe get some dirt under your nails.