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"Every" guide seems to be giving out the codes, I haven't been able to learn what the safes are without exposing myself to spoilers.

Can the safes only be opened by using a correct combination? What type of items they generally hold?

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It kinda seems like you are asking several questions, so I will answer them separately.

Can the safes only be opened by using a correct combination?

Yes (except portable safes, which are opened by minigame). However, each safe combination can be freely found by exploring location.

What type of items they generally hold?

Basically all safes and lockers contain upgrades either to one of your weapons or to your inventory. With exception of portable safes, which give you optional key items.

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  • Are you sure that all codes can be found on the first run (not completing both Leon and Claire scenarios)?
    – user238192
    Oct 2, 2019 at 13:30
  • Yes. Either in documents or in environment (e.g. on photos or chalkboards). During my own first playthrough, I didn't found any lockbox or locker that I was unable to open.
    – lentinant
    Oct 3, 2019 at 12:59

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