Squalo is very loyal to Xanxus, but gets frustrated by Xanxus' abuse. Xanxus relies on him to a certain extent, as seen during the Future Arc when Squalo was apparently in charge of Xanxus' meals. They met at a young age and Squalo grew his hair out as a sign of loyalty to Xanxus. They often insult each other and Xanxus laughed when Squalo almost died after losing to Yamamoto, however in the Curse of the Rainbow Arc he seemed shocked/distraught when Squalo was seemingly killed. But otherwise they work closely together to lead the Varia.
Squalo and Dino were schoolmates in their youth. Dino rescued Squalo in the Varia Arc, and again in the alternate future. Squalo gave Dino a gift of tuna and leaned on Dino after being seriously injured by Zakuro, showing some trust between them. However, there has been minor conflict whenever Xanxus opposed Hibari, Dino's student.
Yamamoto was Squalo's enemy at first, because they were fighting for the right to wield the Rain Vongola Ring. After the Varia's defeat, Squalo became Yamamoto's swordsmanship tutor. Squalo has faith in his student's potential and insists that Yamamoto give up baseball to devote himself completely to the path of the sword. Yamamoto is amused by Squalo's antics but also takes his tutor's advice seriously. Squalo's expertise was crucial in Yamamoto's fight against Genkishi.
Being a loyal follower of Xanxus, Squalo initially didn't support Tsuna's claim to the position of Vongola boss. Since being defeated in the Ring Battles, Squalo and the rest of the Varia have become somewhat reluctant allies to Tsuna and his Guardians. At the Inheritance Ceremony, Squalo noticed Yamamoto's absence; he and Dino then offered their assistance to Tsuna. He was later shown to be displeased when Tsuna refused to wage war on Enma's family.