Well, Alexander's relative (Alexander of Epirus) WAS fighting the Romans and made the comment (according to Plutarch, I believe) that while Alexander was fighting women in the East, HE (Alexander of Epirus) was fighting Men in the West. (and lost, by the way...).
For what it's worth, Pyrrhus, using an Alexandrian-style army (with MUCH less cavalry, in numbers and quality and fewer troops overall than Alex was employing in the East) a generation after Alex the Great did pretty well against Romans who were probably better than they had been a generation before. And, yes, the Samnites were quite a thorn in the side of the Romans in Alex's time and would have probably supported him as they did Pyrrhus later (they were defeating the Romans all by themselves in this era at battles like the Caudine Forks...)
I think the REAL difference would have been tactical leadership and command. Roman commanders during that era were mediocre and their scouting was abysmal. Obviously, Alexander was great in both regards. Also, the Romans were not professionals at this point, and the Macedonians were long-serving veterans.
I do not think it would be a huge contest.