Safari wouldn't open for me at all once I updated to 10.5.3. I don't use any plugins in Safari, so there's no customisation issue.
I tried restarting a couple of times with no luck. Eventually, I shut the computer down completely for an hour or so while updating software on a couple of other Macs in the house. When I restarted the computer again Safari worked fine.
This only happened on one computer, namely my dual 2.5GHz G5, 6GB RAM, OSX 10.5.3.