Lennie are dropped off miles from the ranch where they are going to work.  Their solitude and alienation is symbolized by the location, the vicinity of Soledad in the Salinas Valley. This is the first conflict. Pondering the impersonal and gratuitously cruel treatment to which they have been subjected earlier, George reflects angrily,

"We could just as well of rode clear to the ranch if that bastard bus driver knew what he was talkin' about. 'Jes' a little stretch down the highway,' he says....damn near four miles, tha't what it was!  Didn't wanta stop at the ranch gate, tha't what....Kicks us out and say, 'Jes a little stretch down the road.' I bet it was more than four miles. Damn hot day."

From the beginning, the contrast between George and Lennie is apparent.  With the surnames of Milton and Small, their intelligences are suggested.  Lennie follows George, moving like a bear, submerging his head into the water of the stream and dabbling in it with "paws." These actions of Lennie create the main conflict between the men, one of intelligence.  For, George scolds Lennie, "You gonna be sick like you was last night....You'd drink out of a gutter if you was thirsty."

When Lennie again asks where they are going, George becomes irritated since Lennie has been told several times already. Then, George becomes upset by having seen Lennie take a mouse from his pocket; scolding, he tells Lennie, "Give it here!" These two incidences describe the major conflicts involving George and Lennie:  mentally deficient, the child-like Lennie has difficulty remembering things, and he disobeys George and finds himself in trouble as he was in Weed when he frightened a girl and caused George and his hurried departure. 

Reflecting on the trouble that Lennie has caused him, George says,

"I could get along so easy and so nice if I didn't have you on my tail.  I could live so easy and maybe have a girl."

Yet, if he were alone, George would lose his external conflicts with Lenne, but, then, he would suffer from an internal conflict, that of aloneness.  Similarly, Lennie suffers from this conflict with George as he feels rejection.  In his love for George, he suggests that he could go away and live in a cave; but, of course, he cannot sustain himself, and George realizes that his conflicts with Lennie will never be resolved by leaving.  He must look out for Lennie as the man needs him.

This dilemma of the desire to protect oneself from others while facing solitude is the major conflict of  the characters of Steinbeck's novella.  Deprived of family and friends, the men must be protectively distrustful of each other, yet they also need companionship as they become cruel and aggressive in their alienation.  It is a metaphoric chapter that John Steibeck creates in his first chapter Of Mice and Men, one that represents the need for a brotherhood of men to stave off the solidary deprivations of soul experienced by the itinerant workers of the 1930s.