Poor John Dowell hasn't ever slept with his own wife, but his best friend, Edward, has been sleeping with her for nine years straight. There is a balance between those two characters: out of the two men, one has slept with neither wife, and one has slept with both wives. Dowell is also the narrator, so the reader identifies more with his story than Edward's (not that Edward earns himself much credence; he's pretty easy to dislike). The question on the table seems to be whether Edward will end up happier selfishly trading his integrity for pleasure.
Because the reader identifies more with Dowell than Edward, one might say the novel is about loneliness, frustration, and the jealousy brought on by rejection and betrayal. Dowell certainly understands these things as does Leonora, but where Dowell's marriage atrophied quickly (his wife would never consummate their marriage), Leonora has been dragged along on a string, constantly apologized to and begged for forgiveness. Dowell is far from the issue, making him bitter, cold, and detached, and Leonora is near to the issue emotionally, making her frantic, panicky, and afflicted.
In the end, Dowell earns himself a reward for all his suffering. First, the reader has to remember that Dowell also was in love with Nancy, the woman for whom Edward also left Florence (essentially, both men did). Although she loses her mind over the confusion of her relationship to Edward and his sudden suicide, she agrees to live with Dowell, and Dowell provides for her and protects her while she regains her confidence. The implication is that Dowell will in Nancy, and the protagonist wins.
