Background: Fosfomycin is used as a combination partner for the treatment of severe non-urinary tract infections. Individualized dosing of fosfomycin based on therapeutic drug monitoring (TDM) has the potential to reduce drug-related adverse events (AEs). Methods: This retrospective study used routine data from patients receiving intravenous fosfomycin therapy. Plasma concentrations of fosfomycin were categorized into three different ranges: 128 mg/L. Subsequently, the influence of acute kidney injury (AKI) on reaching the specific plasma concentration ranges and the occurrence of AEs was analyzed. Results: The study included 143 patients (median age 73 years, 66.4% male) with fosfomycin plasma measurements. Beta-lactam antibiotics were most frequently used in combination (62.2%), followed by tetracyclines (12.2%), cotrimoxazole (8.1%), and other agents (17.5%). Fosfomycin concentrations were >128 mg/L in 45% (36/80) of patients with normal renal function, 70.4% (38/54) of patients with AKI stages I to III, and 77.8% (7/9) of patients with renal replacement therapy. AEs occurred in 54% (77/143), mainly hypernatremia (42.6%), hypokalemia (39.9%), and gastrointestinal symptoms (19.6%), with the median fosfomycin plasma concentration being significantly higher in patients with AEs (158 mg/L vs. 131 mg/L, p = 0.01). Multivariate logistic regression analysis revealed that patients aged ≥70 years (OR 3.70, 95% CI 1.24–11.5; p = 0.02) and patients with fosfomycin plasma concentrations > 128 mg/L (OR 3.30, 95% CI 1.09–10.4; p = 0.04) had a higher risk of AEs. Conclusions: There was a significant association between high plasma exposure and the occurrence of AEs. In particular, the impact of acute renal insufficiency on fosfomycin plasma concentrations should be considered. Individualized fosfomycin dosing based on TDM and the intensive monitoring of renal function contribute to reducing drug-related side effects.