Mythbusters did extensive testing on this. They found lower MPG with a removed tailgate, or tailgate down.. as it made more vacuum behind the cab, so tailgate up was actually better. Similar results for a cover or without, but the best MPG was ironically the net tailgate that used to be quite common, not so much any more, but I'd not do one based on practicality. They did precise measurements of fuel and controlled tests.. so to summarize, a cover or tail gate up had similar results, so don't expect a major gain with a cover, but it does have other advantages. I have a Roll N Lock cover, and it is great, but I don't have it expecting a huge MPG gain.