Adults living with sickle cell disease (SCD) have extremely high rates of unemployment; however, very little is known about factors that contribute to their vocational outcomes. This study examined demographic, illness perception, and psychological variables as predictors of employment status among 115 adult respondents who completed a cross-sectional survey as part of the Cooperative Study of Sickle Cell Disease. Logistic regression analysis indicated that gender, assertiveness, and perceived impact of SCD were unique predictors of employment status. Women were 2.88 times more likely to be employed than men, and the odds of being employed increased by a factor of 2.47 for each one unit decrease in assertiveness. More favorable perceptions of SCD were also associated with a two-fold increase in employment. The results suggest that demographic and psychosocial factors may play a more important role in predicting employment outcomes in adults with SCD than previously recognized.