Neoadjuvant systemic therapy may induce steatosis or sinusoid obstruction syndrome in the liver. The aim of this study was to investigate the influence of systemic therapy with irinotecan, oxaliplatin and cetuximab on conspicuity of liver metastases on computed tomography (CT). CT scans of 48 patients with initial unresectable colorectal liver metastases which were treated in a Europe-wide, opened, randomized phase II trial receiving oxaliplatin or irinotecan combined with folinic acid and cetuximab were analysed. The density of the metastases and the liver parenchyma before and after systemic therapy were analysed by region-of-interest technique and the tumour-to-liver difference (dHU TLD). The mean density of liver parenchyma and liver metastases did not vary significantly before and after neoadjuvant therapy on plain (56.3 ± 8.1 HU, 54.8 ± 13.5 HU) and arterial enhanced CT (76.0 ± 15.7 HU, 70.5 ± 20.4 HU). There was a significant reduction (105.6 ± 17.3 HU, 93.3 ± 18.2 HU) in the density of liver parenchyma on portal venous scans after systemic therapy (p < 0.0001) and a reduction of dHU TLD, consecutively. In patients with colorectal liver metastases, neoadjuvant chemotherapy may have a toxic impact on liver parenchyma resulting in reduced tumour-to-liver contrast in contrast-enhanced CT. This may lead to underestimation of real lesion size.