Background The novel coronavirus (SARS-CoV-2) pandemic spread rapidly worldwide increasing exponentially in Italy. To date, there is lack of studies describing clinical characteristics of the people at high risk of infection. Hence, we aimed (i) to identify clinical predictors of SARS-CoV-2 infection risk, (ii) to develop and validate a score predicting SARS-CoV-2 infection risk, and (iii) to compare it with unspecific scores. Methods Retrospective case-control study using administrative health-related database was carried out in Southern Italy (Campania region) among beneficiaries of Regional Health Service aged over than 30 years. For each person with SARS-CoV-2 confirmed infection (case), up to five controls were randomly matched for gender, age and municipality of residence. Odds ratios and 90% confidence intervals for associations between candidate predictors and risk of infection were estimated by means of conditional logistic regression. SARS-CoV-2 Infection Score (SIS) was developed by generating a total aggregate score obtained from assignment of a weight at each selected covariate using coefficients estimated from the model. Finally, the score was categorized by assigning increasing values from 1 to 4. Discriminant power was used to compare SIS performance with that of other comorbidity scores. Results Subjects suffering from diabetes, anaemias, Parkinson’s disease, mental disorders, cardiovascular and inflammatory bowel and kidney diseases showed increased risk of SARS-CoV-2 infection. Similar estimates were recorded for men and women and younger and older than 65 years. Fifteen conditions significantly contributed to the SIS. As SIS value increases, risk progressively increases, being odds of SARS-CoV-2 infection among people with the highest SIS value (SIS = 4) 1.74 times higher than those unaffected by any SIS contributing conditions (SIS = 1). Conclusion Conditions and diseases making people more vulnerable to SARS-CoV-2 infection were identified by the current study. Our results support decision-makers in identifying high-risk people and adopting of preventive measures to minimize the spread of further epidemic waves.