Combofix should be used as a last resort. Inside bleepingcomputer site has at least 3 useful tools to start disinfecting malware and viruses.

Combofix it actually a combination of the anti malware softwares listed in its site. Hence the name Combofix.

You can run combofix in normal windows mode provided the pc does not have aggresive memory resident programs that could disable combofix or any malware cleaner. If you have encountered that kind of virus that disables everything to clean it, that would be hardest and require an external boot disk to clean the hdd.

Running combofix in Safe mode, may or not help in the cleaning process. The 1 camp i know would run it in normal mode so it could catch the memory resident programs in action. The other camp runs it in safe mode citing the saved time bypassing auto loading memory resident malwares. Both has its merits and can be used depending on need.

Some malwares can be packaged together with system Restore and can come back as a repaired anomaly of lost windows files. So disabling System Restore can be done if needed also. Most anti malware programs will scan system restore files these days. But it never hurts to learn old techniques.