Kidney EGFR expression together with reported cases of glomerular diseases in the context of anti-EGFR drug administration raise concerns about the renal safety profile of these drugs. This issue is addressed in a case/non-case study carried out on VigiBase^®, the WHO global database of individual case safety reports (ICRS). Disproportionality analysis of renal adverse effects related to the selected anti-EGFR drugs, erlotinib, gefitinib, afatinib, osimertinib, cetuximab and panitumumab, was assessed using the reporting odds ratio (ROR). Nine hundred and eighty-nine ICRSs were included. A signal of disproportionate reporting (SDR) was found for afatinib (ROR = 2.70; 95% CI [2.22–3.29]) and erlotinib (ROR = 1.73; 95% CI [1.46–2.04]) with acute kidney injury, and for afatinib (ROR = 2.41; 95% CI [1.78–3.27]), cetuximab (ROR = 1.42; 95% CI [1.14–1.78]) and erlotinib (ROR = 2.23; 95% CI [1.80–2.77]) with renal failure. The preferred term “diarrhoea” was frequently reported in the included cases. An SDR was found for erlotinib with haemolytic and uremic syndrome (ROR = 4.01; 95% CI [1.80–8.94]) and thrombotic microangiopathy (ROR = 4.94; 95% CI [2.80–8.72]). No SDR was seen for glomerular or tubule-interstitial diseases. This study showed that the anti-EGFR drug renal toxicity is mainly related to renal failure in the context of digestive toxicity.