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One hundred pigs from the NE Index Line (NEI) and 100 Hampshire-Duroc cross pigs (HD) were inoculated intranasally with porcine respiratory and reproductive syndrome virus (PRRSV 97-7895 strain) at 26 d of age to determine whether genetic variation in response to PRRSV exists. An uninfected littermate to each infected pig served as a control. Pigs were from 163 dams and 83 sires. Body weight and rectal temperature were recorded, and blood samples were drawn from each pig on d 0 before inoculation and on d 4, 7, and 14 after inoculation. Pigs were sacrificed on d 14. Lung and bronchial lymph nodes were collected, placed in optimal cutting temperature compound, and frozen at -80°C. The presence of PRRSV in serum and in lung tissue and bronchial lymph nodes was determined by isolation in cell culture. The presence of antibodies in serum collected on d 14 was determined by a commercial ELISA test. Lung tissue was examined microscopically and scored for incidence and severity of lesions (score of 1 to 3; 1 = no or few lesions, and 3 = severe interstitial pneumonia). Data were analyzed with a mixed model that included random sire and dam effects. The interaction of line × treatment was significant (P< 0.001) for weight change and rectal temperature. Uninfected HD pigs gained 0.67 kg more from d 0 to 14 and averaged 0.32°C higher rectal temperature than uninfected NEI pigs (P < 0.001), whereas infected NEI pigs gained 0.34 kg more and had −0.54°Clower temperature than infected HD pigs (P < 0.001). Viremic titer (cell culture infectious dose 50%/mL) was greater (P < 0.05) in HD than NEI at d 4 (104.52 vs. 104.22), 7 (104.47 vs. 103.99), and 14 (103.49 vs. 103.23). Viral titer loads in lung (P = 0.11) and bronchial lymph nodes tended (P = 0.07) to be greater in HD than NEI pigs. Antibody signal- to-positive (S/P) ELISA ratios in infected pigs ranged from 0.18 to 3.38, and 88% had levels ≥0.40, which is the positive threshold for this ELISA. The S/ P range in uninfected pigs was 0 to 1.11, and 99% had levels ≤0.40. Mean S/P ratio for infected pigs was 0.23 units higher in HD than in NEI (P < 0.001). The HD pigs had a greater incidence of interstitial pneumonia and 0.65 higher mean lesion scores than NEI pigs (P < 0.001). In summary, responses of pigs of the two lines to infection with PRRSV differed, indicating that underlying genetic variation existed.