I don't consider Tobirama to be a real villain... but he definitely was responsible for destroying every opportunity Madara had to be "good." He killed Izuna, and stood as a constant reminder that the score was not equal between Madara/Hashirama. He represented the lack of trust the village had towards Madara, essentially making it impossible for Madara to feel attatchment to Konoha (of the familial sort that Hashirama hoped for, anyway). Tobirama also represented the Senju clan's hatred of the Uchiha, tainting the friendship created by Hashirama... in the end, Hashirama was the only one who stood by Madara, and that alone would have been enough if Tobirama hadn't remained as Hashirama's flesh and blood brother.
It's sad, because as much as Madara doubted that Hashirama could part with his younger brother, even for all of Hashirama's claims that Madara was like a brother to him, I believe that Tobirama felt a similar sort of insecurity... Madara was the one who, in so many ways, stole Tobirama's brother from him, just as Tobirama did to Madara. Madara, unlike Tobirama, was the only one who could challenge Hashirama in battle; compared to the two, Tobirama was powerless. Hashirama was even willing to lay down his life, leaving Tobirama without any family, all to appease Madara for a truce... to Hashirama, this may have been a fair chance to avoid killing his younger brother and still make peace, but it's highly inconsiderate to Tobiraama's feelings.