Pre-existing interstitial lung disease (pre-ILD) increases the risk of chemotherapy-related lung injury (CRLI). However, whether the risk varies by type of anti-cancer cytotoxic agent in patients with pre-ILD is unknown. In this study, we hypothesized that S-1, an oral fluoropyrimidine agent, is associated with a smaller CRLI risk than docetaxel (DTX) and investigated these agents together with radiological evaluations of pre-ILD via pre-treatment chest computed tomography (CT). After reviewing 234 and 352 patients who underwent evaluable chest CT within 6months prior to the administration of S-1 or DTX, respectively, from January 2006 to October 2014, 60 and 89, respectively, of these patients with pre-ILD were retrospectively analysed. In total, 2 persons administered S-1 (3%) and 16 treated with DTX (18%) developed CRLI (p=0.007) after the initial treatment (mean, 61days), of whom 1 and 7, respectively, died because of respiratory failure. Pre-treatment CT revealed that 9 S-1-treated patients (16%) and 15 DTX-treated patients (17%) had pre-ILD occupying more than 25% of the lung field. Multivariate analysis demonstrated that DTX administration increased the risk of CRLI by 6.47-fold versus S-1 therapy (p=0.016). Of note, the area occupied by pre-ILD was also associated with the risk of CRLI (<25%; odds ratio 0.309, p=0.045). Our results indicated that S-1 is associated with a smaller risk of CRLI than DTX. The area occupied by pre-ILD should also be noted when administrating anti-cancer agents.