"In the coming days reconstructive surgery will be planned," an Inter statement said.
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Samuel, the latest in a string of Inter players to be injured, went down in severe pain after landing on a straightened leg in Saturday's 1-1 Serie A home draw with Brescia.
The defender was out for almost a year after suffering a similar injury in 2007.
Since coming back Samuel has formed a fearsome central defensive partnership with Lucio which was key to Inter winning the Champions League, Serie A and Italian Cup last term.
Ivan Cordoba looks set to deputise for Samuel in the short term with Marco Materazzi and Cristian Chivu the other options at centre-back, unless Inter decide to buy in January.
Right-back Maicon also went off injured against Brescia and tests have shown the Brazilian has strained a thigh muscle, meaning he could be out for some weeks.
Last term's treble winners were without five injured midfielders against Brescia and the latest news comes as a big blow to new coach Rafael Benitez, who has rejected criticism that his training methods may be to blame for all the injuries.
Inter, gunning for their sixth straight scudetto this season, suffered fewer injuries under former coach Jose Mourinho.
