Well, they will try their hands at the colonial game, of course.
I've been wondering if the Eighty Years' War would be butterflied away or not, but it depends on how the Reformation goes (ITL it begins in the Swiss Confederacy, not Saxony).
Not completely, IOTL there were more than just religious reasons for the Eighty Years' war. Most of them were political, the majority of the Catholics wasn't happy with Philip II either; but protestants and catholics also didn't trust eachother and that become worse as the conflict progressed.
Furthermore OTL Philip II never had the same respect in the Low Countries as his father Charles V, who was from the region (born in Ghent (Gent), raised in Malines (Mechelen)...). ITTL the Habsburgs will have more reason to visit the region, and Brussels could become a serious competitor of Vienna for the position/title of 'capital of the Habsburg empire'*.
Anyway ITTL the Habsburg rulers will keep in touch with the region; and it is in their best interest since it is one (perhaps the most) wealthy region the rule ITTL.
And with no OTL Charles V ITTL, the Habsburgs will also focus more on the Holy Roman Empire in general...
*= a final point is that now the Habsburgs and Aviz-Trastamaras have rulers, which don't have to travel in the same manner as the OTL Charles, could we expect new or improved Aviz-Trastamara and Habsburg palaces to rival their counterparts in England and France? Since IOTL Charles V, who had to travel constantly, never had the opportunity to build palaces to rival England and France.