Chronic inflammatory reactions have been proven to represent relevant mechanisms for the development and progression of cancer in numerous tumor entities. There is evidence that the platelet-to-lymphocyte ratio (PLR) is associated with the prognostic outcome. In rectal cancer, the prognostic role of this parameter has not yet been conclusively clarified. The aim of this study was to further clarify the prognostic significance of the pre-treatment PLR in patients with locally advanced rectal cancer (LARC). In the present study, 603 patients with LARC, who were treated with neoadjuvant chemoradiotherapy (nCRT) and subsequent surgical resection between 2004 and 2019, were retrospectively evaluated. The influence of clinico-pathological and laboratory factors on locoregional control (LC), metastasis-free survival (MFS) and overall survival (OS) was investigated. In univariate analyses, high PLR was significantly associated with worse LC (p = 0.017) and OS (p = 0.008). In multivariate analyses, the PLR remained an independent parameter for the LC (HR = 1.005, 95% CI: 1.000-1.009, p = 0.050). Pre-treatment lactate dehydrogenase (LDH) (HR: 1.005 95% CI:1.002-1.008; p = 0.001) and carcinoembryonic antigen (CEA) (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) were independent predictors for MFS; additionally, age (HR: 1.052, 95% CI:1.023-1.081; p < 0.001), LDH (HR: 1.003, 95% CI:1.000-1.007; p = 0.029) and CEA (HR: 1.006, 95% CI:1.003-1.009; p < 0.001) independently predicted OS. Pre-treatment PLR before nCRT is an independent prognostic factor for LC in LARC, which could be used to further individualize tumor treatment.