Systemic lupus erythematosus was diagnosed in a 34-year-old pregnant woman because of leukopenia, typical skin rash, clinical and biochemical signs of muscle involvement, and positive serology (antinuclear antibodies and anti-double-stranded DNA). Corticosteroids and hydroxychloroquine (HCQ) were started at 18 weeks of gestation with overall benefit except for muscle involvement, which proved resistant even to higher dose of corticosteroids and high-dose intravenous immunoglobulin. Muscle biopsy showed signs of HCQ toxicity, and the drug was stopped. After withdrawal, muscle involvement disappeared. Hydroxychloroquine could be safely reintroduced some months after delivery. It is hypothesized that pregnancy may have represented the second "hit" in this patient with systemic lupus erythematosus necessary for the rapid development of HCQ-related myopathy.