I am wanting to "close off" unused rooms in my house to help lower cooling and heating costs. I just am unsure if this is that effective. Do I just close off the vents blowing out cool/hot air, or should I close/cover the cold air return too? It is a four bedroom house, where only two bedrooms are used.

Closing off the out vents should make some positive difference to heating costs, assuming you keep the doors of those rooms closed. Depending on where you live though you might find that the rooms get damp in winter if they're not being heated at all.

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Energy Saving Trust ~ BBC Homes ~ Looking at double glazing