Background: Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. CRC cells produce immunoregulatory GC, a process regulated by nuclear receptor liver receptor homolog-1 (LRH-1). Additionally, LRH-1 plays a critical role in the control of cell cycle and tumorigenesis. Therefore, CRC cells have a strong steroidogenic potential and tumor-derived GC may contribute to tumor immune evasion. Thus, we aim to evaluate whether variations in LRH1 and GC receptor (NR3C1) genes may predict outcome in mCRC patients treated with first-line FOLFIRI and bevacizumab (bev). Methods: Genomic DNA from whole blood samples was obtained from 378 mCRC patients who were treated with FOLFIRI/bev in the TRIBE (discovery cohort; N = 215, female/male 83/132; median age 60; median follow-up 48.9 months) and MAVERICC (validation cohort; N = 163, female/male 60/103; median age 62; median follow-up 23.3 months) trials, and subsequently genotyped through the OncoArray, a custom array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of six selected SNPs in LRH1 and NR3C1 genes were analyzed. Results: In the discovery cohort, patients carrying NR3C1 rs10041520 any C showed a longer OS compared to T/T variant in the univariate analysis (28.9 months vs 20.5 months, HR = 0.69, 95%CI = 0.50-0.97, P = 0.029). LRH1 rs2737656 any T variant showed longer PFS compared to C/C genotype in multivariate analysis (10.3 months vs 9.4 months, HR = 0.62, 95%CI = 0.41-0.93, P = 0.020). Patients carrying any G in LRH1 rs2690034 showed shorter OS compared to those carrying C/C variant in multivariate analysis (25.0 months vs 29.8 months, HR = 1.46, 95%CI = 1.02-2.10, P = 0.040). The NR3C1 rs10041520 findings were validated in the MAVERICC FOLFIRI/bev arm. Here, patients carrying any C variants had a longer OS compared to T/T genotype in multivariate analysis (27.9 months vs 26.5 months, HR = 0.42, 95%CI = 0.19-0.92, P = 0.030). Conclusions: Our results provide the first evidence that the genetic variants within NR3C1 and LRH-1 genes might serve as a prognostic/predictive markers in patients with mCRC treated with first-line FOLFIRI and bevacizumab.