| 07 Sep 80 | r01        | New Orleans SaintsNew Orleans S | 23 - 26 | San Francisco 49ersSan Francisco |
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| 14 Sep 80 | r02        | San Francisco 49ersSan Francisco | 24 - 21 | Arizona CardinalsArizona Cardi |
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| 21 Sep 80 | r03        | New York JetsNew York Jets | 27 - 37 | San Francisco 49ersSan Francisco |
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| 28 Sep 80 | r04        | San Francisco 49ersSan Francisco | 17 - 20 | Atlanta FalconsAtlanta Falco |
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| 05 Oct 80 | r05        | Los Angeles RamsLos Angeles R | 48 - 26 | San Francisco 49ersSan Francisco |
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| 12 Oct 80 | r06        | Dallas CowboysDallas Cowboy | 59 - 14 | San Francisco 49ersSan Francisco |
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| 19 Oct 80 | r07        | San Francisco 49ersSan Francisco | 17 - 31 | Los Angeles RamsLos Angeles R |
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| 26 Oct 80 | r08        | San Francisco 49ersSan Francisco | 23 - 24 | Tampa Bay BuccaneersTampa Bay Buc |
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| 02 Nov 80 | r09        | Detroit LionsDetroit Lions | 17 - 13 | San Francisco 49ersSan Francisco |
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| 09 Nov 80 | r10        | Green Bay PackersGreen Bay Pac | 23 - 16 | San Francisco 49ersSan Francisco |
| 16 Nov 80 | r10        | Miami DolphinsMiami Dolphin | 17 - 13 | San Francisco 49ersSan Francisco |
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| 23 Nov 80 | r12        | San Francisco 49ersSan Francisco | 12 - 0 | New York GiantsNew York Gian |
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| 30 Nov 80 | r13        | San Francisco 49ersSan Francisco | 21 - 17 | New England PatriotsNew England P |
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| 07 Dec 80 | r14        | San Francisco 49ersSan Francisco | 38 - 35 | New Orleans SaintsNew Orleans S |
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| 14 Dec 80 | r15        | Atlanta FalconsAtlanta Falco | 35 - 10 | San Francisco 49ersSan Francisco |
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| 21 Dec 80 | r16        | San Francisco 49ersSan Francisco | 13 - 18 | Buffalo BillsBuffalo Bills |