The Heidelberg–Neckargemünd section of the line was built in 1862 as part of the Baden Odenwald Railway (Baden Odenwaldbahn), running from the Heidelberg via Neckargemünd, Meckenheim, Neckarbischofsheim, Aglasterhausen, Obrigheim, Neckarelz, Mosbach, Oberschefflenz, Seckach, Osterburken, Königshofen and Lauda to Würzburg.
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In a few years, the Rhine-Neckar S-Bahn network is expected to be reorganised so that S-Bahn services on the Neckar Valley Railway no longer run on the Palatine Ludwig Railway to Kaiserslautern; instead they will run from Schifferstadt via Speyer to Germersheim and later to Bruchsal.
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