I will stand against the tide and say BRP CoC is the best way to play it. Why, you ask?
Skill and atmosphere.
Skill is the cornerstone of the CoC universe. Heroes are almost universally academics, experts, explorers, or some other learned or mentally exceptional individuals. At the same time, the creatures of the Mythos are horrifying abominations who can slay these characters almost at will (mentally or physically). The skills the characters have and develop through their experiences with the Mythose really are the cornerstone of their "power" rather than BAB, saving throws or other various d20 metagame measures.
The Cthulhu universe is inherently nihilistic, and BRP really ensures that it reflects in play. Seperation from DnD is vital to keeping the right atmosphere at the table. I have a 4 year old d20 gaming group, and they all know how things basically work, what they can survive, when to run, etc. The metagame is all figured out. With BRP, my players understand much less of the metagame - no one reads the critter descriptions other than the GM - and so are much more cautious and focused on behaving in a "realistic" manner. This style of play actually improves the mood at the table as well, as we're all walking on eggshells already waiting for the next horrible thing to happen.
I see folks saying the d20 version is better for campaigns, and I reckon it is if you define "campaigns" by the characters who survive the entire story. BRP campaigns tend to rotate casts as characters are driven mad by encounters with Things That Must Not Be Named, killed by cultists, consumed by animals or simply burnt out by going to places that man was never meant to experience. This falls right in line with my envisioning of the Lovecraft universe, where I would fully expect the rigors adventurers experience to retire individuals quickly, but groups to endure regardless. Delta Green really is the epitome of this ethos, where Delta Green keeps sending agents into the grinder in the hopes that one day someone will get lucky enough to break it. Fun
PLUS, BRP CoC has some of the best modules ever made. The Masks of Nyarlathotep and Delta Green are simply incredible, and some of the best supplements ever created for ANY game. We're starting the Shadow of Yog-Soggoth this week, and I can't wait. I don't expect my first character to survive til the end, but I'll surely enjoy the ride