CONTEXT:Little is known about the phenotypic and molecular characteristics associated with various domains of quality of life (QOL) in women after breast cancer surgery. OBJECTIVES:In a sample of women with breast cancer (n = 398), purposes were as follows: to identify latent classes with distinct trajectories of QOL from before surgery through six months after surgery and to evaluate for differences in demographic and clinical characteristics, as well as for polymorphisms in cytokine genes, between these latent classes. METHODS:Latent class analyses were done to identify subgroups of patients with distinct QOL outcomes. Candidate gene analyses were done to identify cytokine gene polymorphisms associated with various domains of QOL (i.e., physical, psychological, spiritual, social). RESULTS:One latent class was identified for the psychological and spiritual domains. Two latent classes were identified for the social domain and overall QOL scores. Three latent classes were identified for the physical domain. For the physical and social domains, as well as for the overall QOL scores, distinct phenotypic characteristics (i.e., younger age, poorer functional status, higher body mass index, and receipt of adjuvant chemotherapy) and a number of cytokine gene polymorphisms (CXCL8, NFKB2, TNFSF, IL1B, IL13, and NFKB1) were associated with membership in the lower QOL classes. CONCLUSIONS:Findings suggest that women experience distinctly different physical well-being, social well-being, and total QOL outcomes during and after breast cancer surgery. The genetic associations identified suggest that cytokine dysregulation influences QOL outcomes. However, specific QOL domains may be impacted by different cytokines.