Creating a full setup package for a program is almost a subject area in itself. There are many factors to consider and most of us aren't running Windows 95 anymore. The world is not as simple as it once was.
There are a lot of things that need to be addressed, and some of these "setup" issues mean changing the program too. For example the "protected folders" concept that seemed to be new to people when Vista UAC came on the scene. I guess they were all running as admin or something? In its simplest form it means you don't put writeable files next to the EXE in Programs (aka "Program Files") anymore.
Another factor is that the way the registry is used has changed. I'm not talking about registry virtualization, though that's part of it as well. But COM registration can be done both per-machine and per-user and even turning UAC off can muck this up. See Per-User COM Registrations and Elevated Processes with UAC on Windows Vista SP1. The result is that a setup package shouldn't be running regsvr32 (or otherwise calling the self-reg entrypoint of a COM library). See "Remarks" at SelfReg Table.
Windows Installer is the way to go forward in most cases. VB6 programmers have Visual Studio Installer 6.0 version 1.1 available as a free download for creating MSI packages. See "COM Servers" at the VFP article Using Microsoft Visual Studio Installer for Distributing Visual FoxPro 6.0 Applications for some valuable information.
This isn't the easiest option but there is a VB Setup Wizard in VSI 1.1 to help get the basics right. Doing advanced things like creating a [CommonAppData] subfolder and setting Everyone rights on it has to be done in a post-build step outside the IDE. That's where 3rd party tools can be useful to give you more control without resorting to Orca or post-build Installer scripts.
Those guys making scripted "legacy" installers try to keep up, but the scripting gets more and more complicated. The results are sometimes iffy. Windows 7 introduces a few new wrinkles of its own.
While ClickOnce isn't really the best option for VB6, nothing says you can't use reg-free COM for XCopy installs of many programs. Reg-free COM can even be a good option for use in an Installer package for that matter.
So in the end the "simplest" way to deploy VB6 programs is probably going to be reg-free COM XCopy packages wrapped in a self-extracting EXE that will fire off a script to create a Start Menu shortcut. If you can live without the shortcut this is even easier: just unzip the package where it needs to go!
See Make My Manifest or alternative tools for reg-free COM packaging.
This requires that the target systems be running XP (preferably SP2) or later. The only possible glitch here is that XP did not include the VB6 SP6 runtimes until XP SP3, so you'll want to test your program against the VB6 SP5 runtimes first. Well one more glitch: you can't use ActiveX EXEs this way, they still require registration.