Many of the landmarks were removed.
Most of the clothes from SR3 were removed or dumbed down into outfits. (I have no idea why they did it).
Some of the vehicles from SR3 were removed. (Condor, Taxi hell they even removed all the boats).
Much like how most of the activites in SR3 were escort missions (snatch, gaurdian angel, trafficking, and the ever-so-awful escort) most of the activites in SR4 was just the Mayhem activity repeated ad-nauseum.
Weather effects were extremely bland and bad compared to what we got in past games.
Instead of a large variety of enemies like in SR3 (Morningstar Snipers, Police Riot Units, Luchador Grenadiers, Decker Elites, STAG Commandos, Brutes and regular old grunts) we have grunts that look identical to one another and special units that were more annoying than fun to fight (this could be the reason why many of the npc mods on here get rid of or tone down the Wardens, Marauders and Murderbots).
Seems to be less stable with mods than SR3. (Couldn't tell you how many times my game crashed.)
DLC Mission Packs were much shorter than any of the SR3 Mission Packs.
Pulls an SR3 were important characters from past games never make an appearance or are very briefly shown\mentioned For example Oleg, Birk, Viola, Zimos, Dex, Troy and the SR3 dlc characters (Jimmy, Jenny, Genki Girls, Tammy).