Longitudinal case-control studies were performed in post-weaning multisystemic wasting syndrome (PMWS) affected farms from Denmark and Spain using similar designs. Fourteen independent batches of 100-154 pigs per batch were monitored from birth to PMWS outbreak occurrence. Pigs displaying PMWS-like signs and matched healthy cohorts were euthanized during the clinical outbreak. PMWS was diagnosed according to internationally accepted criteria and pigs were classified as: (i) PMWS cases, (ii) wasted non-PMWS cases and (iii) healthy pigs. Porcine circovirus type 2 (PCV2) quantitative PCR (qPCR) and serology techniques were applied to analyse longitudinally collected sera and/or nasal and rectal swabs. Results showed that PCV2 load increased in parallel to waning maternal antibody levels, reaching the maximum viral load concurrent with development of clinical signs. PMWS affected pigs had higher PCV2 prevalence and/or viral load than healthy pigs in all collected samples at necropsy (p < 0.0001-0.05) and even in sera and nasal swabs at the sampling prior to PMWS outbreak (p < 0.01-0.05). Danish farms had a higher PCV2 prevalence in young piglets as well as an earlier PMWS presentation compared to Spanish farms. PMWS diagnoses were confirmed by laboratory tests in only half of pigs clinically suspected to suffer from PMWS. Positive and significant correlations were found among PCV2 viral loads present in sera, nasal swabs, rectal swabs and lymphoid tissues (R = 0.289-0.827, p < 0.0001-0.01), which indicates that nasal and rectal swabs were suitable indicators of PCV2 excretion. Sensitivity and/or specificity values observed from both tests used separately or combined suggested that qPCR and/or serology tests are not apparently able to substitute histopathology plus detection of PCV2 in tissues for the individual PMWS diagnosis within PMWS affected farms. However, qPCR appears to be a potential reliable technique to diagnose PMWS on a population basis.