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Introduction Hyponatremia is a common condition of varying etiology among hospitalized patients and is associated with adverse outcomes. Treatment to normalize serum sodium is advisable. Tolvaptan received European Union marketing authorization for hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Post-marketing pharmacovigilance activities were required to characterize the safety profile of tolvaptan more fully in this population, which is often elderly with a high burden of comorbid illness. Methods This was a prospective, observational, multinational, post-authorization pharmacovigilance study (NCT01228682) in seven European countries. Hospitalized patients were enrolled who received tolvaptan for hyponatremia associated with SIADH and consented to data collection. Tolvaptan was initiated and assessments performed at physician discretion per local standards of care. To reflect actual clinical practice, no assessments or procedures were required outside the standard of care. Patients who continued to receive long-term tolvaptan following hospital discharge and provided consent received follow-up from their community physicians. Results A total of 252 patients (mean age 70.6 years) enrolled. Mean tolvaptan treatment duration was 139.4 days, median 18.5 (range 1–1130) days; most frequent dose was 15 mg/day (used in 75% of patients). Serum sodium increased from baseline (mean 123.2 mmol/l) during treatment week 1 and remained stable during follow-up, with little difference across doses of 7.5, 15, and 30 mg/day. Hyponatremia symptoms (e.g., confusion, unsteady gait, lethargy) were present in 122/252 (48.4%) patients at pre-treatment baseline, decreasing to 46/252 (18.3%) during treatment. Sixty-two patients (24.6%; mean baseline serum sodium 120 mmol/l) experienced rapid correction of hyponatremia within 72 h. No osmotic demyelination syndrome occurred. Conclusion In clinical practice, tolvaptan improved serum sodium and decreased hyponatremia symptoms in hyponatremia secondary to SIADH. Serum sodium should be monitored during treatment to minimize risk of rapid correction. Trial Registration Clinicaltrials.gov identifier NCT01228682. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01947-9., Plain Language Summary Hospitalized patients often experience abnormally low blood sodium levels (hyponatremia), which can cause significant symptoms and poses a serious health risk (Wald et al. in Arch Intern Med 170:294–302, 2010). Yet, increasing sodium levels too rapidly in these patients can unintentionally cause osmotic demyelination syndrome, resulting in long-term neurologic damage or death. Tolvaptan was approved in the European Union to treat one type of hyponatremia caused by a hormonal imbalance known as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Tolvaptan effectively increased patient sodium levels in clinical trials, but real-world data are needed to understand tolvaptan treatment more fully in everyday clinical practice. We evaluated patterns of use, efficacy, and safety of tolvaptan in patients treated in hospitals and after discharge for hyponatremia due to SIADH. Tolvaptan was correctly used to treat only hyponatremia caused by SIADH in nearly all of the 252 patients studied. Patient sodium levels increased in the first week of tolvaptan treatment and then stabilized. Hyponatremia symptoms, such as confusion, nausea, tiredness, and dizziness, were present in 48.4% of patients before treatment and in 18.3% after starting tolvaptan. Consistent with earlier studies, some patients (24.6%) experienced excessively rapid correction of hyponatremia. However, no subsequent neurologic problems or deaths were attributed to the rapid correction, which suggests that medical providers were carefully monitoring and managing sodium levels to prevent serious consequences. Our study indicates that tolvaptan is being used safely and effectively to treat hyponatremia due to SIADH in a patient population with complex medical needs. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01947-9.