As highly pathogenic avian influenza (HPAI) spreads in US dairy herds, substantial uncertainty remains regarding modes of transmission and net impacts on cattle health and productivity. The objectives of our study were to identify factors associated with risk of clinical HPAI diagnosis (cHPAI) among lactating cows and quantify subsequent productivity and health outcomes of cHPAI versus nonclinical (NC) cows. We used herd management data from a dairy farm in Michigan (44.8 ± 10.4 kg/d ECM, 1.58 ± 0.04 SCS before outbreak; mean ± SD) that experienced an HPAI outbreak in May 2024. Over 13 d, 28.3% of the herd´s lactating cows (932/3,293) exhibited clinical signs and were treated for HPAI. Univariate analysis demonstrated greater risk of diagnosis for multiparous versus primiparous cows (odds ratio [OR] 2.36; 95% CI 1.97–2.82); pregnant versus not (OR 1.45; 1.25–1.70); ≥100 DIM versus <100 DIM (OR 1.66; 1.41–1.95); and greater milk yield (OR 1.013 per kilogram per day; 1.005–1.021). Multivariate modeling retained parity, the quadratic effect of DIM, and pregnancy status as risk factors for cHPAI diagnosis. After accounting for DIM, pregnancy tended to be protective rather than increasing risk of HPAI diagnosis (OR 0.71; 0.54–0.92), with peak risk occurring for nonpregnant cows in their fifth lactation at 220 DIM. Effects of HPAI diagnosis in the same lactation were assessed with data from 9 test days from May 2024 to January 2025 in a model that also included parity and the quartic fit of DIM, with repeated measures within cow. At 25 d after onset, cHPAI cows produced 15.1 ± 0.40 kg/d less ECM, and SCS increased 1.89 ± 0.07 units (mean ± standard error of the difference) relative to NC cows. The SCS no longer differed between groups at 98 d post-onset, but ECM yield remained significantly different through 224 d after the outbreak (?4.60 ± 0.63 kg/d). Primiparous cows had a lesser ECM reduction than multiparous cows (?2.05 ± 0.60 vs. ?7.39 ± 0.66 kg/d for parity 1 vs. 3). Protein concentrations increased subtly in cHPAI cows at 25 d and 56 d post-outbreak compared with NC. Clinical HPAI cows had a 1.74-fold greater hazard (95% CI 1.16–2.62) of death and a 2.61-fold greater hazard (95% CI 2.16–3.16) of culling during the ongoing lactation compared with NC. Clinical HPAI and NC cows did not differ in the odds of abortion, mastitis, or having at least 1 adverse health event. In summary, primiparous cows were at lesser risk for cHPAI and suffered less production losses than multiparous cows. Milk production of cHPAI cows was impaired for more than 7 mo after HPAI onset, far longer than the effects on SCS. Clinical HPAI diagnosis was strongly associated with subsequent hazards of death and culling. Our findings provide insight into the magnitude and duration of milk production impacts in one large herd while also providing novel insights into cow-level factors linked to risk of clinical HPAI.