Purpose The aim of this study was to assess splenic volume and to correlate unidimensional measurements with reference volumetric changes in chemotherapy-treated patients with colorectal cancer (CRC) liver metastases. Methods Forty consecutive patients were selected from the cohort of a previously reported study of chemotherapy-related morbidity following major hepatectomy for CRC liver metastases. Patients were treated for 6 months prior to resection, with imaging performed at baseline and after 6 months of chemotherapy. Three unidimensional spleen measurements were recorded—width, thickness, and height (W, T, and H). Reference splenic volume was measured at baseline and after chemotherapy. The best unidimensional splenic measurement was determined by regression analysis. The 95% CI for the predicted values and R2 values was calculated for each regression. The percentage of volume increase at 6 months was calculated. Results W and H showed the highest correlation with splenic volume prior to and following chemotherapy (R2 = 0.65–0.74, p < 0.001), while T showed a low correlation (R2 = 0.11 and 0.18, p < 0.05). The mean reference splenic volume increased after 6 months of chemotherapy compared to baseline (326 vs. 278 mL). Splenic volume changes showed the highest correlation with changes in W (R2 = 0.56, p < 0.001), then H (R2 = 0.40, p < 0.001), but were not significantly correlated with changes in T (R2 = 0.01, p = 0.055). Conclusions Our results show the potential utility of measuring changes in splenic width to predict clinically significant changes in splenic volume in chemotherapy-treated patients with CRC liver metastases.