A biennial experiment (2009 and 2010) was conducted at Calvi (Benevento, Southern Italy) to evaluate the effect of compost by organic fraction municipal solid waste (OFMSW), in combination with mineral nitrogen (N) fertilization, on yield and quality of three Dark Fire-cured (Kentucky) tobacco cultivars commonly cultivated at Benevento province (Campania region, Southern Italy). Six N fertilization treatments (N0 = soil N reserves available for plant growth; MIN = 135 kg ha−1 of N applied as mineral fertilizer; C10 = 10 Mg d.w. ha−1 compost; C10N = 10 Mg d.w. ha−1 compost + 50% MIN; C20 = 20 Mg d.w. ha−1 compost; C20N = 20 Mg d.w. ha−1 compost + 50% MIN) were combined with the following cultivars: (i) Foiano, medium early maturing; (ii) Riccio Beneventano (local ecotype), medium maturing; (iii) SKL, medium maturing. Yield of cured leaves (Mg ha−1) and growth components (number of leaves per plant, mean individual leaf area, leaf area per plant, specific leaf weight, stem diameter and height) and color parameters (L*, a*/b*) were measured. Leaf quality traits (nitrates, total N and alkaloids contents, score) and N use efficiency were also determined. The best growth and yield performance was reached in 2010 when plants were taller, developed both stems that were more robust and leaves having greater individual leaf area, and showed a higher leaf area per plant than in the first year. Regardless of the form of applied N (compost, mineral fertilizer, or a combination of both), tobacco plants appeared to be directly and positively influenced by increasing quota of readily available N received by each treatment, which was determined at the beginning of field growth by N soil balance and taking into account the percentage of N supplied by organic (compost) and mineral fertilizers. Results obtained with compost treatments, particularly when combined with mineral fertilizer (at C10N more than C20N), appeared comparable or sometimes better than those of full mineral fertilization although N fertilization by synthetic products was applied at very low doses.