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Because inflammation and fibrosis have been linked to the progression of osteoarthritis, we investigated the effects of oral Pirfenidone in a mouse model of cartilage injury, which results in chronic inflammation and joint\u2010wide fibrosis in mice that lack hyaluronan synthase 1 (Has1<jats:sup>\u2212\/\u2212<\/jats:sup>) in comparison to wild\u2010type. Femoral cartilage was surgically injured in wild\u2010type and Has1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, and Pirfenidone was administered in food starting after 3 days. At 4 weeks, Pirfenidone reduced the appearance, on micro\u2010computed tomography, of pitting in subchondral bone at, and cortical bone surrounding, the site of cartilage injury. This corresponded with a reduction in fibrotic tissue deposits as observed with gross joint surface photography. Pirfenidone resulted in significant recovery of trabecular bone parameters affected by joint injury in Has1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, although the effect in wild\u2010type was less pronounced. Pirfenidone also increased Safranin\u2010O staining of growth plate cartilage after cartilage injury and sham operation in both genotypes. Taken together with the expression of selected extracellular matrix, inflammation, and fibrosis genes, these results indicate that Pirfenidone may confer chondrogenic and bone\u2010protective effects, although the well\u2010known anti\u2010fibrotic effects of Pirfenidone may occur earlier in the wound\u2010healing response than the time point examined in this study. Further investigations to identify the specific cell populations in the joint and signaling pathways that are responsive to Pirfenidone are warranted, as Pirfenidone and other anti\u2010fibrotic drugs may encourage tissue repair and prevent progression of post\u2010traumatic osteoarthritis. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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