Abstract Purpose: Increasing research suggests that inflammation mediates symptom development. In this longitudinal study, we examined inflammatory factors related to the development of high symptom burden during autologous hematopoietic stem cell transplant (AuSCT) for multiple myeloma. Experimental Design: Patients (n = 63) repeatedly reported symptom severity on the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM) and contributed blood samples periodically for up to 100 days after AuSCT for inflammatory marker assays. The temporal associations between serum inflammatory marker concentrations and symptom severity outcomes were examined by nonlinear mixed-effect modeling. Results: Fatigue, pain, disturbed sleep, lack of appetite, and drowsiness were consistently the most severe MDASI-MM symptoms during the study. Peak symptom severity occurred on day 8 after AuSCT, during white blood cell count nadir. Patterns of serum interleukin (IL)-6 (peak on day 9) and soluble IL-6 receptor (sIL-6R; nadir on day 8) expression paralleled symptom development over time (both P < 0.0001). By univariate analysis, serum IL-6, sIL-6R, IL-10, C-reactive protein, macrophage inflammatory protein (MIP)-1α, sIL-1R2, sIL-1RA, and soluble tumor necrosis factor receptor 1 were significantly related to the most severe symptoms during the first 30 days after AuSCT (all P < 0.05). By multivariate analysis, IL-6 (estimate = 0.170; P = 0.004) and MIP-1α (estimate = −0.172; P = 0.006) were temporally associated with the severity of the component symptom score. Conclusions: Systemic inflammatory response was associated with high symptom burden during the acute phase of AuSCT. Additional research is needed to understand how the inflammatory response is mechanistically associated with symptom expression and whether suppression of this response can reduce symptoms without compromising tumor control. Clin Cancer Res; 20(5); 1366–74. ©2014 AACR.