There is limited information regarding chickens inter and intra-breed resistance to fowlpox virus (FWPV). Incidentally, it was observed during a natural fowlpox outbreak in a flock of inbred Isa White chickens having different plumage colors that those with predominantly white plumage were most severely affected. Thus, this study assessed the effects of plumage color in progenies of the affected chickens on immune response and severity of fowlpox virus infection. Thirty each of white and colored chickens were selected from the same hatch and challenged experimentally with a field fowlpox virus. Fifteen chickens from each plumage group were vaccinated against fowlpox prior to challenge while the remaining unvaccinated half were infected with the field virus. Vaccine ‘takes' diameters, discrete fowlpox lesions and FWPV antibody titer were evaluated. The highest mean vaccine ‘takes' in white (9.95 ± 0.34 mm) and colored (10.74 ± 0.41 mm) chickens were observed on day-7 post-vaccination. White chickens had lower mean antibodies to fowlpox virus pre- and post-vaccination (21.83 ± 3.32 and 41.61 ± 6.16 ng/L) than colored chickens (26.89 ± 5.47 and 53.25 ± 7.26 ng/L), however, the difference was not statistically significant (p ˃ 0.05). While, mean fowlpox lesions count differed significantly (p ˂ 0.05) between white (4.00 ± 0.56) and colored (2.0 ± 0.35) chickens. Immune responses and severity of fowlpox are likely influenced by plumage color in Isa White breed of chickens.