Hydrochlorothiazide is a sulfonamide and can be absorbed systemically. Sulfonamides can produce severe, possibly fatal, reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome.

Hydrochlorothiazide is often used in combination, e.g. with aliskiren (Tekturna HCT); amiloride (Moduretic); benazepril (Lotensin HCT); bisoprolol (Ziac); captopril (Capozide); enalapril (Vaseretic); irbesartan (Avalide); lisinopril (Prinzide and Zestoretic); losartan (Hyzaar); methyldopa (Aldoril); moexipril (Uniretic); spironolactone (Aldactazide); triamterene (Dyazide and Maxzide).