Background: Hematopoietic Stem Cell Transplantation (HCT) is a potentially curative treatment for certain hematologic cancers. Although survival rates are markedly higher than in the past, there are a growing number of long-term HCT survivors who are at risk for short and long-term sequela, which can negatively affect quality of life. Psychoneurological (PN) symptoms are common occurrences associated with heightened inflammation in other cancers and chronic conditions. Emerging research links the gut microbiota to inflammatory biomarkers and suggests that gut-microbiota-brain crosstalk impacts the severity of psychoneurological symptoms among HCT recipients. Methods: This longitudinal descriptive study investigated the relationship among a cluster of PN symptoms (pain, fatigue, and depression), inflammatory biomarkers (IL-6, IL-10, C-reactive protein (CRP), and microbiota diversity measures (Shannon and Chao Beta diversity indexes) in 55 individuals receiving HCT for a hematologic malignancy. The time periods examined covered pre-transplant, 30-days, and 100-days following transplant. The PN symptoms were collected through self-reported questionnaires via computer with assistance from study staff, along with blood samples and stool specimens obtained at each study visit. Inflammatory marker values were log-transformed when used as dependent variables. Gut microbiota samples were analyzed using 16S ribosomal gene (V4 region) amplicons using Illumina MiSeq. Data analysis was performed using SAS 9.4, with PROC MIXED used for the mixed model analyses. Results: The analysis characterized mean changes in microbiota diversity over time for both Shannon and Chao indexes. IL6 levels were consistent over time, with an inverse association with Chao but not Shannon index. IL10 and CRP levels changed over time, but without associations with either Shannon or Chao. Pain severity and interference changed over time, but with no associations with inflammatory markers or gut microbiome beta diversity. Fatigue severity and interference changed over time and were positively associated with IL10. Depression did not change over time and was not associated with inflammatory markers or diversity. Conclusions: This study provides preliminary information related to associations between PN symptoms, inflammatory markers, and selected measures of gut microbiome diversity in HCT recipients. Further research is needed to explore and validate these findings to examine the implications for microbiota diversity on inflammatory factors and PN symptoms. Clinical trial information: NCT02398708.