Hamsters were infected with SARS-CoV-2 by the intranasal route (I). (A) HCQ (T) was administered either prophylactically 1 time at 24 hours before infection (6.5 mg/kg and 50 mg/kg) or as a treatment starting 1 hour after infection and continuing every 24 hours for 3 consecutive days (6.5 mg/kg and 50 mg/kg). Hamsters were scored for clinical signs daily and swabs (oral and rectal) were collected 48 and 96 hours after infection (S). Animals were euthanized on day 4 and lungs were harvested for pathology and virology. Swab and lung loads were determined by qRT-PCR. (B and C) Viral shedding. Oral and rectal swabs collected on days 2 and 4 were analyzed for viral genome copies by qRT-PCR. (D) Percent weight change. Hamsters were weighed daily as a parameter to measure disease progression. Daily weights were compared with starting weights to generate a percent change. (E) Viral load in lung tissue. Lung viral loads (E assay, genome copies) were determined as a correlate for lower respiratory tract infection. (F) Infectious lung titers. Lung samples were titrated for infectious virus. No statistical significance was found between the groups presented in parts B–F. (G) Lung-to-body weight ratio. Lung-to-body weight ratio was determined as an indicator for pneumonia with lung edema. Statistically significant differences were found only when compared with lung-to-body weight ratios of naive hamsters. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; HCQ, hydroxychloroquine; qRT-PCR, quantitative reverse transcriptase PCR.