Objectives were to evaluate effects of replacing 40 ppm of zinc from zinc sulfate (CON) with zinc amino acid complex (Zn; Availa-Zn, Zinpro Corp., Eden Prairie, MN) on production, SCC, and metabolism following an i.v. lipopolysaccharide (LPS) challenge in lactating cows. Cows were enrolled in a 2 × 2 factorial design and assigned to 1 of 4 treatments: 1) pair-fed (PF) control (PF-CON; 5 mL saline; n = 5), 2) PF Zn (PF-Zn; 5 mL saline; n = 5), 3) LPS-euglycemic clamp control (LPS-CON; 0.375 μg/kg BW LPS; n = 5), 4) LPS-euglycemic clamp Zn (LPS-Zn; 0.375 μg/kg BW; n = 5). A pre-feeding phase (42 d) was included before initiation of the experimental phase, and then cows were enrolled in 3 experimental periods. During P1 (3 d), cows received their respective dietary treatments and baseline data were obtained for covariate analysis. During P2 (2 d), a 12-h LPS-euglycemic clamp was conducted or cows were PF to their respective dietary counterparts to eliminate effects of dissimilar nutrient intake. During P3 (3 d), cows consumed feed ad libitum and received their respective dietary treatment. LPS administration decreased DMI (47%) during P2, and by experimental design, the pattern was similar in PF cohorts. DMI of LPS cows remained decreased (15%) throughout P3 relative to PF cows (P = 0.03). Milk yield from LPS cows decreased (54%) during P2 relative to PF cows, but treatments did not differ during P3. During P2, SCC increased (3-fold) in LPS cows, relative to PF controls (P < 0.01). Between 54 and 72 h post-LPS, Zn supplementation tended to decrease (70%) SCC relative to LPS-CON cows (P = 0.10). Insulin increased 7-fold in LPS cows at 12 h post-LPS and remained increased (4-fold) for the duration of P2 relative to PF cows (P = 0.01). NEFA in LPS-Zn cows remained at baseline, while in all other treatments it gradually increased (P = 0.02). The 12-h total glucose deficit, quantified immediately post-LPS, was 36 and 1,606 g for the PF and LPS treatments, respectively, but glucose utilization was not influenced by Zn. In summary, supplemental Zn tended to reduce milk SCC following immunoactivation, with no evidence of altering production or metabolism.