An ecological design was used to study the relationship between cancer incidence and both socio-economic and environmental features in Southern Spain. Twenty-four sites and 26,380 cases diagnosed in 1985–1996 were analysed. Generalised Additive Models were used for data analysis. Except for lip cancer, the urban areas showed an increase in cancer risk for all sites. The relative risks among urban and rural municipalities ranges between 1.09 for skin non-melanoma (95% CI: 1.00–1.18) and 1.64 for cervix cancer (95% CI: 1.28–2.12). The relative risk among areas with high and low unemployment was 1.29 for stomach cancer (95% CI: 1.07–1.57), 1.45 for oral cavity cancer (95% CI: 1.10–1.93) and 1.77 for oesophagus cancer (95% CI: 1.02–3.05). Areas with highest unemployment showed the lowest incidence of melanoma. Risk for leukaemia, gall bladder, breast and prostate cancer showed a significant decreases by approximately 28% in the municipalities with the highest illiteracy score. A high percentage of land under cultivation was related to uterine tumours, larynx, rectum, lung, skin non-melanoma and brain cancers. For these sites, the risk had a significant increase by between 23% (skin non-melanoma) and 70% (rectum). Areas with high intensive farming showed a significant increase in cancer risk for lip, oral cavity, larynx, oesophagus, colon, lung, and bladder cancer. The relative risks ranges between 1.16 for colon cancer (95% CI: 1.04–1.29) and 1.47 for oesophagus cancer (95% CI: 1.15–1.87). The results of this study reveal how important socio-economic and environmental factors are for the analysis of cancer incidence in small areas of Southern Spain.