Background Some experts recently reported that SARS-CoV-2 lethality decreased considerably, but no evidence is yet available. This retrospective cohort study aimed to evaluate whether SARS-CoV-2 case-fatality rate decreased with time, adjusting for main potential confounders. Methods and findings We included all SARS-CoV-2 infected subjects diagnosed in Ferrara and Pescara provinces, Italy. Information were collected from local registries, clinical charts, and electronic health records. We compared the case-fatality rate of the subjects diagnosed during April and March, 2020. We used Cox proportional hazards analysis and random-effect logistic regression, adjusting for age, gender, hypertension, type II diabetes, major cardiovascular diseases (CVD), chronic obstructive pulmonary diseases (COPD), cancer and renal disease. The sample included 1946 subjects (mean age 58.8y; 45.7% males). 177 persons deceased, after a mean of 11.7 days of follow-up. From March to April, the case-fatality rate significantly decreased in the total sample (10.8% versus 6.0%; p<0.001), and in any subgroup of patients. Large reductions of the lethality were observed among the elderly (from 30.0% to 13.4%), and subjects with hypertension (23.0% to 12.1%), diabetes (30.3% to 8.4%), CVD (31.5% to 12.1%), COPD (29.7% to 11.4%), and renal disease (32.3% to 11.5%). In April, the adjusted hazard ratio of death was 0.42 (95% Confidence Interval: 0.29-0.60). The mean age of those who died substantially increased from March (77.9y) to April (86.9y). Conclusions In this sample, SARS-CoV-2 case-fatality rate decreased considerably over time, supporting recent claims of a substantial improvement of SARS-CoV-2 clinical management. The findings are inevitably preliminary and require confirmation.