This observational study evaluated the characteristics of genotype 4 chronic hepatitis C (CHC) patients and their response to combination therapy in Spain. 383 patients with CHC, 44 with genotype 4-HCV infection, were investigated. Nineteen genotype 4-HCV infected patients received IFNalpha-2b (3 MU three times weekly) plus ribavirin (1-1.2 g/day) and ten received Peg-IFNalpha-2b (1.5 microg/kg/week) plus ribavirin (1-1.2 g/day) for 12 months. A sustained virological response (SVR) was evaluated. Genotype 4-HCV was detected in 11.5% of patients, and was significantly associated with a higher proportion of infection through intravenous drug use (46% vs 11%; p<0.001), a higher alcohol intake (35% vs. 7%; p<0.001), higher proportion of anti-HBc positivity (41% vs. 22%; p<0.05), lower ALT (87+/-50 vs. 139+/-142 IU/L; p<0.001) and AST (53+/-30 vs. 85+/-126 IU/L; p<0.001) levels, lower viremia (4.1 +/- 7.7 (x 10(5)) vs . 7.3 +/- 9.8 IU(x 10(5) )/mL) p<0.05) and less fibrosis (stage 3-4 in 21% vs. 32%; p<0.06). Sixteen (55%) out of the 29 patients treated with combination therapy achieved a sustained virological response (SVR) while 10 (36%) were non-responders and 3 (9% relapsed. In conclusion, the lower stage of fibrosis, lower viremia and higher SVR rate than genotype 1 suggest a less aggressive pattern of diseased caused by this genotype.