Abstract The influence of sex and reciprocal cross type were evaluated in Brahman-sired (B × A) and Angus-sired (A × B) F1 cattle following modified-live viral vaccination regarding virus neutralization titers (VNT) and cell-mediated immune (CMI) responses following in vitro exposure to Bovine Viral Diarrhea Virus (BVDV) Type 1 (BVDV1) and Type 2 (BVDV2) genotypes. VNT against BVDV were based on virus neutralization assay, and CMI responses were measured using the PrimeFlow mRNA assay for determination of the frequency of BVDV and interferon-gamma (IFN-γ) positive cells. Mixed model procedures utilized individual calf ID as a random effect with fixed effects of F1 cross type, calf sex, evaluation date, and potential 2-way interactions; models for frequency of BVDV and IFN-γ positive cells, stimulation conditions (BVDV1, BVDV2, mitogen, none) and potential two-way and three-way interactions of fixed effects. Relationships of immune responses with calf birth weight and weaning weight and steer carcass traits were also investigated. This study found several CMI traits differed due to the type of cross and calf sex; however, no differences in VNT were attributed to these effects. Cells from B × A animals consistently ranked approximately 20% greater for BVDV positive cells (BVDV+) than those from A × B animals pre-MLV vaccination; however, post-MLV vaccination, cells from A × B animals ranked 20% greater (P < 0.05) for CD2+, CD4+, and CD8+ cells. Post- MLV steers consistently had 30 to 35% greater (P < 0.05) frequencies of BVDV+ cells following viral exposure; steers had greater frequencies (P < 0.05) of CD4+ and CD335+ cells expressing IFN-γ and ranked greater for CD2+ and CD8+ cells when compared with heifers in both crosses. Only vaccination timing affected BVDV VNT. No significant correlations involving VNT and CMI responses were observed among A × B animals when stimulated with BVDV1, but among B × A animals, positive correlations were observed with IFN-γ in CD4+ (r = 0.406, P = 0.049) and CD335+ (r = 0.472, P = 0.020). When stimulated with BVDV2, positive correlations of 0.33 to 0.39 (P < 0.05) were observed between BVDV and IFN-γ frequency within cell type; these were not significant when stimulated with BVDV1, except for CD335+ cells (r = 0.41, P = 0.003). No correlations for VNT and CMI responses were observed when stimulated with BVDV2. No major correlations between immune responses and weight or carcass traits were observed, and immune response category for BVDV or IFN-γ frequency did not influence birth weight or weaning weight. Differences in CMI responses involving reciprocal cross types and sex observed in this project may relate to widely reported reciprocal cross differences in birth weight in Bos indicus - Bos taurus crossbred cattle and warrant additional study.