A key theme in On the Road is friendship. The close friendships that Sal forms with Dean and the other characters bind them together. The friendship group that includes Sal, Dean, Carlo, and Roland comes together in multiple cities at various times, which shows that the bond between them defies simple geography or opportunity. Sal chases off across the country in search of these friends, and when they’re not with him, he misses them terribly. Denver feels cold and empty to him without his friends, suggesting that friendship rather than some innate quality of the city is what matters. The many intertwining and interconnected friendships are the bedrock on which the narrative is built. The novel illustrates how these friendships give meaning to the places the characters visit and the journeys they take.

The closest friendships in the novel are often the most intense, and most involve Dean. At first, Carlo Marx is closest to Dean, and they have long, interrogating conversations that last until dawn. They share everything together, to the point that they may as well be talking nonsense. Though they extract meaning and substance from these sessions, anyone who watches is bemused and then bored.