Background This paper concerns the spatial determinants of the first two waves of COVID-19 at the neighbourhood level. Methods Using data for the first and second waves of COVID-19 at the neighbourhood level in Barcelona, we analyse whether local characteristics acted in the same way during the two waves and identify typologies of areas depending on such determinants. Univariate and bivariate local Moran’s I and count data models are used. Results Some structural effects at the neighbourhood level consistently either boost (e.g. population density) or reduce (e.g. income) COVID-19 cases. Other effects differ between the two waves (i.e. age composition, schools and transport infrastructures). Conclusions Since certain characteristics influenced the virus diffusion in opposite ways between the two pandemic waves, territorial heterogeneity alone is insufficient to explain COVID-19 outbreaks—individual behaviour also needs to be factored in. Consequently, both econometric and spatial analysis techniques are recommended for tracking the spatiotemporal spread of this disease and for monitoring the effectiveness of policy measures across heterogeneous neighbourhoods.