This prospective study of chemotherapy-induced neutropenia (CIN) explored the association between the relative grade of neutropenia and symptom burden and quality of life (QOL). Eighty-four adult cancer patients from nine community oncology centers receiving 1 of 13 myelosuppressive chemotherapies were evaluated at days 0, 4, 7, 9, 11, 14, and 21 of their respective first cycle. Neutropenia grade (grade 3/4 vs grades 0 to 2) was determined by serial absolute neutrophil count (ANC) measures. Measures of patient-reported outcomes included the Rotterdam Symptom Checklist (RSCL), Hospital Anxiety and Depression Scale (HADS), Cancer Care Monitor-Medical Isolation Scale (CCM-MIS), and SF-36. Changes in outcomes from baseline to highest grade of neutropenia were evaluated using mixed model-repeated measures for each of 15 outcomes. Compared with grades 0-2, grade 3/4 neutropenia was associated with greater symptom burden and worse QOL for six measures (P < 0.05). The pattern of differences suggested that measures of symptom distress and social functioning were sensitive to patient changes associated with grade 3/4 neutropenia. Worsening of symptom burden and QOL appears to be associated with severe afebrile neutropenia. A causal relationship between neutropenia and worse symptoms and QOL remains difficult to establish due to the confounding of the effects of neutropenia with other adverse effects of chemotherapy.