This study sought to determine if there was an association between prognostic-based serum biomarkers, survival, and psychosocial factors in patients with metastatic renal cell carcinoma. Associations were found between psychosocial factors and biomarker levels (hemoglobin with depressive symptoms (r = −0.29), positive affect (r = 0.30), social support (r = 0.19), and perceived stress (r = −0.27); albumin with depressive symptoms (r = −0.19), positive affect (r = 0.22), and social support (r = 0.20); alkaline phosphatase with depressive symptoms (r = 0.21), all p values <0.05. After adjustment for disease-related risk factors, only the associations between positive affect and perceived stress with hemoglobin remained significant (p’s < 0.05). Positive affect (HR = 0.90; 95 % CI = 0.83, 0.97; p = 0.009) and depressive symptom total scores (HR = 1.03; 95 % CI = 1.01, 1.06; p = 0.013), and alkaline phosphatase (HR 2.72; 95 % CI = 1.41, 5.24; p = 0.003) were associated with survival. This study suggests that measures of positive and negative psychological outlook may contribute differently to health, well-being, and survival.