How to clear exisiting dropdownlist items when its content changes?

You should clear out your listbbox prior to binding:

 Me.ddl2.Items.Clear()
  ' now set datasource and bind

Please use the following

ddlCity.Items.Clear();

Using ddl.Items.Clear() will clear the dropdownlist however you must be sure that your dropdownlist is not set to:

AppendDataBoundItems="True"

This option will cause the rebound data to be appended to the existing list which will NOT be cleared prior to binding.

SOLUTION

Add AppendDataBoundItems="False" to your dropdownlist.

Now when data is rebound it will automatically clear all existing data beforehand.

Protected Sub ddl1_SelectedIndexChanged(sender As Object, e As EventArgs)
    ddl2.DataSource = sql2
    ddl2.DataBind()
End Sub

NOTE: This may not be suitable in all situations as appenddatbound items can cause your dropdown to append its own data on each change of the list.

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TOP TIP

Still want a default list item adding to your dropdown but need to rebind data?

Use AppendDataBoundItems="False" to prevent duplication data on postback and then directly after binding your dropdownlist insert a new default list item.

ddl.Items.Insert(0, New ListItem("Select ...", ""))