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Objectives Men with castrate-resistant prostate cancer (CRPC) suffer from symptoms related to both their disease and its treatment with marked variation between individuals with respect to symptom expression. This study aimed to determine whether genetic variation in cytokine expression is associated with symptom severity.Methods An exploratory prospective, longitudinal consecutive patient cohort study was undertaken across two Queensland sites. Patient characteristics including tumour burden and current treatment were collected at baseline. Symptom severity was assessed 3–4 weekly for up to 6 assessments, with blood taken for genetic analysis once only during the study. Cytokine gene variants of each participant were assessed using a panel of single nucleotide polymorphisms (SNPs) most described in the literature.Results Of the 66 participants, 27/66 (41%) had a low, and 39/66 (59%) a high tumour burden. Symptom severity was not related to tumour burden or patient characteristics. Of the 142 SNPs analysed from 62 participants, 15 SNPs from 7 genes were significantly associated with symptom severity. After Benjamini-Hochberg adjustment, SNPs rs2069772 from Interleukin-2 (IL2) and rs230494 from Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFKb) remained significant.Conclusion Although multiple factors can influence symptom severity, genetic variation may play a part. The early identification of men likely to develop severe symptoms during the course of their prostate cancer could theoretically enable symptoms to be managed more aggressively from an early stage. These preliminary findings need to be replicated in a larger cohort of men with CRPC.