This study aimed to evaluate the effects of the dietary inclusion of grape seed, alone or in combination with linseed, on milk production traits, immune response, and liver and kidney metabolic activity of lactating ewes. Twenty-four Sarda dairy ewes were randomly assigned to 4 dietary treatments consisting of a control diet (CON), a diet containing 300 g/d per head of grape seed (GS), a diet containing 220 g/d per head of extruded linseed (LIN), and a diet containing a mix of 300 g/d per head of grape seed and 220 g/d per head of extruded linseed (MIX). The study lasted 10 wk, with 2 wk of adaptation period and 8 wk of experimental period. Milk yield was measured and samples were collected weekly and analyzed for fat, protein, casein, lactose, pH, milk urea nitrogen, and somatic cell count. Blood samples were collected every 2 wk by jugular vein puncture and analyzed for hematological parameters, for albumin, alkaline phosphatase, bilirubin, creatinine, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, protein, blood urea nitrogen, and for anti-albumin IgG, IL-6, and lymphocyte T-helper (CD4(+)) and lymphocyte T-cytotoxic (CD8(+)) cells. On d 0, 45, and 60 of the trial, lymphocyte response to phytohemagglutinin was determined in vivo on each animal by measuring skin-fold thickness (SFT) at the site of phytohemagglutinin injection. Humoral response to chicken egg albumin was stimulated by a subcutaneous injection with albumin. Dietary treatments did not affect milk yield and composition. Milk urea nitrogen and lactose were affected by diet × period. Diets did not influence hematological, kidney, and liver parameters, except for blood urea nitrogen, which decreased in LIN and increased in MIX compared with CON and GS. Dietary treatments did not alter CD4(+), CD8(+), and CD4(+)-to-CD8(+) ratio. The SFT was reduced in GS and MIX and increased in LIN compared with CON. The IgG and IL-6 were affected by diet × period. The reduction in IgG on d 60 and SFT in ewes fed GS suggests an immunomodulatory effect of this residue. The limited variation in milk and hematological and metabolic parameters suggests that GS and LIN can be included, alone or in combination, in the diet of dairy ewes without adverse effects on milk production and health status.