Let's not mince words: Weisenburger's Companion is utterly essential for any trip through Pynchon's megaton novel. Large swathes of the book which I would have woozily drifted past with 0% comprehension were opened up brilliantly -- it really does help the scope of the entire book to know about business collusions during WWII, as well as the basics of the Kabbalah, Teutonic mythology, the Tarot, Herero folklore, and elementary ballistic physics. These aren't just look-how-clever-I-am cul de sacs, but wide ranging attempts to order a very complex world, to harness the knowledge of the centuries to a violent urge that has plagued humankind since we first climbed out of the sea.
Previous Pynchon books could be read and enjoyed with less fleecy outerwear -- V. can be easily traversed with the help of Pynchonwiki (as well as a Wiki-level knowledge of the Fashoda Conflict, the Herero uprising, and what a Baedekker travel guide looks like). In fact, J. Kerry Grant's guides to V. and The Crying of Lot 49 are almost detrimental in that they attempt to pad their pages with endless recounting of current theories about Pynchon's work (fine to read after you've finished, but annoying when you're in the middle of your first read and attempting to draw your own conclusions). By comparison, Weisenburger does draw some of his own lines, but they're really only attempt to calculate why Pynchon made references to Hansel & Gretel here, not what that means to the modern reader, if you get that hair-thin distinction.
I still think it helps to read V. before this, but at the very least, have this book nearby. I don't think you need to have both open at the same time, but if you read a section of the book, then glance through Weisenburger's info right after, you should be able to transpose the knowledge back into what you just read. Occasionally, the reference opened up the passage enough that I found it beneficial to re-read the book section, but that was rare.
By comparison with the first two, Weisenburger's guide is so thorough, the Pynchonwiki entries have been reduced to little more than hair-splitting with Weisenburger's Companion. I found it amusing to read their entries in the voice of The Simpson's Comic Book Guy.
I'm not going to give it five stars because, as Christgau said about Flavor Flav's role in Public Enemy, "why should I like the Great Man's Fan better than I like the Great Man?" Still, as Robert Stack used to say, "don't leave home without it." (don't leave The Zone without it?)