If you are on a system that correctly implements flock() and you use the example appending code from "perldoc -f flock" everything will be OK even if the OS you are on doesn't implement append mode correctly (if such a system exists.) So if you are happy to restrict yourself to OSs that implement flock() (and that's not really much of a restriction) then that is what you should do.
If you know you are only going to use a system that does correctly implement appending (i.e. not Win32) then you can omit the seek() from the above code.
If you know you are only writing code to run on an OS and filesystem that does implement append mode correctly (a local filesystem on a modern Unix for example), and you keep the file in block-buffered mode and you write less than one buffer-full of output between each manual flushing of the buffer then each bufferload is almost guaranteed to be written to the end of the file in one chunk without getting intermingled with anyone else's output. You can also use the syswrite() function which is simply a wrapper around your systems write(2) system call.
There is still a small theoretical chance that a signal will interrupt the system level write() operation before completion. There is also a possibility that some STDIO implementations may call multiple system level write()s even if the buffer was empty to start. There may be some systems where this probability is reduced to zero.