The SARS-CoV-2 pandemic catalyzed the rapid development and deployment of serological assays, which have been pivotal for monitoring antibody responses to infection and vaccination, guiding vaccine design, and shaping public health strategies. Historically, serum and plasma samples have been considered largely interchangeable in serological testing. However, the precise extent of their similarity or potential differences in antibody detection and quantification remains not fully characterized. This distinction is critical as the choice of sample type carries practical and economic implications, particularly in large-scale seroprevalence studies. To address this, we evaluated IgG, IgM, and IgA antibodies targeting key SARS-CoV-2 antigens (spike, RBD, and N) and assessed neutralization efficiency in 124 paired serum and plasma samples collected simultaneously. Using both manual and automated serological and neutralization assays, we demonstrated that while serum and plasma differ in recovered volume, this difference does not affect antibody concentration or functional neutralization. Our findings confirm that serum and plasma are effectively interchangeable for SARS-CoV-2 serological studies, providing robust evidence to support streamlined, flexible, and cost-effective study designs without compromising data accuracy.