Treatments for chronic hepatitis C (CHC) patients intolerant to pegylated interferons (peg-IFNs) are lacking. Thus, such patients remain at high risk of developing an advanced and decompensated liver disease. Leukocyte IFN-alpha (Le-IFN-alpha) seems to possess a safer profile than other natural and recombinant a-interferons, but no information is available for peg-IFN intolerant patients. Accordingly, we evaluated the safety and efficacy of Le-IFN-alpha in patients intolerant to peg-IFNs. Twenty-five consecutive CHC patients intolerant to peg-IFNs were prospectively enrolled. HCV genotype 1 was present in 80% and cirrhosis in 68% of cases. Thirteen patients (52%) had thrombocytopenia. Le-IFN-alpha (3 MU three times a week) was administered for 48 weeks plus ribavirin 800 or 1,000 mg/day for HCV genotype 2/3 and 1, respectively. The follow-up was at 24 weeks. Compliance with treatment was satisfactory if the patient received 80% of the therapeutic regimen. An intention-to-treat analysis was done. Eighty-eight percent of CHC patients completed the prescribed treatment course with Le-IFN-alpha. In these patients the side effects, when observed, were mild to moderate, and did not require Le-IFN-alpha dose adjustment. Le-IFN-alpha showed significantly less hematological toxicity than peg-IFN (4 vs 48%; P<0.02). The overall sustained virologic response was 32%, i.e., 24% for cirrhotics and 50% for CHC, and 25% for genotype 1 and 60% for genotypes 2/3. The data indicate that Le-IFN-alpha plus ribavirin is a useful and effective treatment for CHC patients who are intolerant to peg-IFNs.