The aim of this study is to describe the epidemiological profile, clinical characteristics, and microbiological findings in African immigrants newly arrived to Spain attended at a specialized reference unit from October 2004 to February 2017. A common protocol for the screening of imported and cosmopolitan diseases was designed to evaluate patients with ≤ 12 months of stay in Spain. A total of 523 patients were included in the study, 488 (93.3%) of sub-Saharan origin. A high number of helminthic infections were diagnosed in sub-Saharan patients, including geohelminthiasis (hookworms 14.3%; Trichuris trichiura 4.1%; Ascaris lumbricoides 3.1%), schistosomiasis (12.3%), strongyloidiasis (17.2%), and filariasis (8.4%). Thirty-five patients (7.2%) had malaria, most by Plasmodium falciparum. Among communicable diseases, 33.6% of sub-Saharans presented HBsAg positivity compared with 5.7% of North African patients (P = 0.001). Thirteen patients were diagnosed with active tuberculosis. Seventy percent of the sub-Saharans and 40% of the North Africans who were tested had a latent tuberculosis infection (LTI). Treatment of LTI was administered in selected cases (14%), achieving end of treatment in 80% of them. In light of these results, effective screening strategies, particularly within the sub-Saharan immigrant population, including potentially communicable diseases and certain potentially serious parasitic diseases (Strongyloides, Schistosoma), should be implemented. It is necessary to facilitate fully and free of charge access to the public health system to newly arrived immigrants, as well as to implement programs and actions aimed at favoring care and follow-up, especially for communicable diseases. Empirical treatment of some parasitic diseases could be a cost-effective action.