WinPatrol (free and paid) has real-time protection BillP Studios - WinPatrol 2012
It checks for system changes.
I've read some people feel there are too many popup warnings.
I don't have that problem.
It depends on how much you install/uninstall programs, make system configuration changes, etc.
You can try it for free and see how you like it.
Malwarebytes offers free and a paid versions.
The free version does NOT have real-time protection.
The paid (Pro) version does have real-time protection.
The Pro version is a one-time fee, lifetime license, no annual fees.
If you are using the free version you could upgrade to Pro.
If you play around with new programs a lot you could also consider
Using a VM (Virtual Machine)
Browser configuration and add-ons can also help with additional security.
Common sense, safe surfing, and reading before clicking are the best protection.
Look through the threads in Security Basics - Windows 7 Forums