Purpose <p>The present study aimed to examine (a) how fatigue severity changes during the course of chemotherapy in patients with hematologic cancer and (b) whether cytokines (IL-1 alpha, IL-1 beta, IL-6) are associated with fatigue change after controlling for demographic and clinical factors (e.g., hemoglobin/hematocrit, medications, comorbid conditions).</p> Methods <p>This observational cohort study used data from 148 hematological cancer patients four times: prior to chemotherapy, on the last day of chemotherapy, 1&#xa0;week after the chemotherapy completion, and 1&#xa0;month after baseline assessment. Latent growth curve modeling was used to examine the longitudinal association of fatigue severity with cytokines and hemoglobin.</p> Results <p>A quadratic growth curve model fit the data well, indicating model tenability, and explained a large amount of variance in fatigue across measurement time points. Fatigue slightly increased toward the end of chemotherapy and decreased with time after chemotherapy completion. The influence of IL-6 on fatigue was significant at all time points except at the last assessment occasion (i.e., 1&#xa0;month after the baseline assessment). The influence of IL-6 on fatigue was independent (unique) from the impact of hemoglobin level. Age and chemotherapy given for the first line of treatment significantly influenced the rate of fatigue change over time. Age also influenced the change pattern’s shape.</p> Conclusions <p>Fatigue severity changes across the course of chemotherapy within the context of IL-6 activity, not the hemoglobin level. The influence of IL-6 may be limited during and shortly after chemotherapy. These findings inform the development of new symptom management strategies.</p>