Well, in the TL I'm working on right now, I'm planning for Barcelona to end up as an island of Protestantism in a mostly-Catholic Spain (basically, the Inquisition doesn't have authority in Catalonia, so the few Spainish (and some Southern French) protestants flee there...), but I think the OP wanted a predominantly Protestant Spain rather than just a little bit of Protestantism...
I think the suggestion earlier that the Pope needs to be allied with an enemy of Spain is a good one. Here's a couple of factors, which, put together might make the difference:
1) No inquisition. For whatever reason the rulers use some other (less repressive) method to deal with crypto-Jews, crypto-Muslims and heretics. What about a system where non-Catholics simply have to pay more tax (I seem to recall the Ottoman empire used this system for non-Muslims), although I forget waht it was called. That would actually give the government an economic incentive to encourage non-Cahtolics.
2) A reconquista which is easier and over sooner. This would mean that Spaniards wouldn't feel the need to be united against a common foe.
3) A less unified Spain with a larger number of smaller states. Maybe Leon, Castille, Aragon, Catalonia, Navarre, could all remain separate. Especially if these separate states feared domination by a foreign power (France?) which also controlled the Papacy.
4) A series of Popes which alienate the Spanish people. Again, if the Pope is dominated by France that would definitely help, but the Pope could also implement specific anti-Spanish policies. Like demanding that all land won in the reconquista belongs to the church or something like that.
5) A King who wants an annulment the Pope won't grant (I don't know if this would work as well in Spain as it did in England, but perhaps).