Wastewater-based epidemiology (WBE) has been implemented to monitor surges of COVID-19. Yet, multiple factors impede the usefulness of WBE and quantitative adjustment may be required. We aimed to model the relationship between WBE data and incident COVID-19 cases, while adjusting for confounders and autocorrelation. This nationwide WBE study includes data from 40 wastewater treatment plants (WWTPs) in Belgium (02/2021–06/2022). We applied ARIMA-based modelling to assess the effect of daily flow rate, pepper mild mottle virus (PMMoV) concentration, a measure of human faeces in wastewater, and variants (alpha, delta, and omicron strains) on SARS-CoV-2 RNA levels in wastewater. Secondly, adjusted WBE metrics at different lag times were used to predict incident COVID-19 cases. Model selection was based on AICc minimization. In 33/40 WWTPs, RNA levels were best explained by incident cases, flow rate, and PMMoV. Flow rate and PMMoV were associated with −13.0 % (95 % prediction interval: −26.1 to +0.2 %) and +13.0 % (95 % prediction interval: +5.1 to +21.0 %) change in RNA levels per SD increase, respectively. In 38/40 WWTPs, variants did not explain variability in RNA levels independent of cases. Furthermore, our study shows that RNA levels can lead incident cases by at least one week in 15/40 WWTPs. The median population size of leading WWTPs was 85.1 % larger than that of non‑leading WWTPs. In 17/40 WWTPs, however, RNA levels did not lead or explain incident cases in addition to autocorrelation. This study provides quantitative insights into key determinants of WBE, including the effects of wastewater flow rate, PMMoV, and variants. Substantial inter-WWTP variability was observed in terms of explaining incident cases. These findings are of practical importance to WBE practitioners and show that the early-warning potential of WBE is WWTP-specific and needs validation. Display omitted •Wastewater-based epidemiology (WBE) for COVID-19 was applied across Belgium.•Wastewater flow rate and population dynamics explain variability in RNA levels.•Variants did not explain variability in RNA levels in 38/40 WWTPs.•WBE metrics lead incident cases by at least one week in 15/40 WWTPs.•Inter-WWTP variability was observed in terms of lead time and optimal metric.