Like other East African countries, Sudan experienced circulation of more than one topotype of SAT2 foot-and-mouth disease virus (FMDV). In Sudan, topotype XIII of SAT2 virus was recorded in 1977 and 2008 and topotype VII in 2007, 2010, 2013, 2014 and 2017. This work evaluated the impact of such diversity on diagnosis and control. After one or three doses of a vaccine derived from a Sudanese SAT2 virus of topotype VII originated in 2010, heterologous neutralizing antibody titres with Sudanese SAT2 viruses in 2008 were ≤ 1.2 log 10, not consistent with likely protection. Simultaneously, homologous titres were 1.65 (after one dose) or 1.95 and 2.55 log10 (after 3 doses). When r1 values between the vaccine virus and the SAT2 viruses isolated in 2008, whilst topotype XIII was circulating, were derived, values (≈ 0.00) suggested similarly poor antigenic relationship and unlikely cross protection. Concurrently, SAT2 positive field sera from Sudan in 2016 were not unvaryingly identified by virus neutralization tests (VNT) employing SAT2 viruses from 2010 and 2008. Proportions of positive sera by SAT2 virus from 2010 were always higher than those by viruses from 2008; consistent with the more frequent and recent circulation of topotype VII prior to 2016. Proportions by SAT2 virus from 2010 were 0.68 (± 0.1) in one location (n = 72), 0.39 (± 0.1) in another one (n = 94) and 0.52 (± 0.1) in the whole test group (n = 166). Corresponding values by viruses of 2008 were 0.53 (± 0.1), 0.27 (± 0.1) and 0.38 (± 0.1). In the whole test group, differences were statistically significant (p = .02339). Like post-vaccination sera, field sera (natural immunity) showed no considerable cross neutralization between topotype VII and presumably XIII; almost 45% (43/96) of SAT2 positive field sera were positive to one topotype but not to the other. Experimental and surveillance findings emphasized the implication of SAT2 diversity in Sudan. It is concluded that it is difficult to control SAT2 infection in Sudan using a monovalent vaccine. Beside a prophylactic vaccine from topotype VII, stockpiling of antigens from topotype XIII and enhanced virological surveillance with rapid genotyping and matching studies are necessary approaches. When more frequent circulation of more than one SAT2 topotype occurs, retrospective diagnosis by serological surveys could be problematic or imprecise.