In pre-trial hearings, Hernandez's lawyers have argued prosecutors have no evidence as to what was in the box.
"I mean, who knows?" co-counsel James Sultan told the court. "It could be drugs, it could be something that was connected to this crime that he knew about, that he was covering up for somebody else after the fact. There are all kinds of possibilities ... But that's not probable cause that he committed murder."
Authorities did seize other guns from the former tight end's home and apartment, as well as .45 caliber ammunition. Hernandez also has pleaded not guilty to five other weapons-related charges.
Unlike the missing weapon in the Lloyd case, police have found a .38 caliber gun they accuse Hernandez of using to kill Safiro Furtado and Daniel Abreu in Boston in July 2012. Police have not established a connection between the gun and Hernandez.
Hernandez is charged as the sole shooter in that case and has pleaded not guilty.
Can prosecutors persuade a jury in the Lloyd case that they don't need to see the weapon involved?
"Given the large number of TV shows devoted to crime ... jurors are always receptive to the popular defense argument that 'missing evidence' creates reasonable doubt in prosecutor's case," said CNN analyst and former New York prosecutor Paul Callan.
Yet, Callan added, authorities can argue there was plenty of time to ditch the weapon.
"After all we still haven't found Jimmy Hoffa, so explaining away a missing gun is not particularly difficult if other evidence is compelling and persuasive," he said.