A more successful war with the Turks potentially gives him significantly more land in Hungary.
Making his wife heiress to Portugal requires significantly more early deaths and her living longer, but would effectively give him control of the Portuguese colonial empire (instead of having it wait for his son Philip). For less ambitious colonial gains, a more successful resolution to the Moluccas dispute might lead to a more favorable Treaty of Zaragoza.
Maybe switch he and his brother's wives? That way Charles V also becomes King of Bohemia and Hungary.