Background: iNHLs are a heterogenous group of incurable diseases with prolonged illness courses requiring intermittent periods of surveillance and treatment. Due to illness uncertainty, patients with iNHL struggle with immense psychological distress. Yet, studies exploring coping, prognostic uncertainty and distress in this population are limited. Methods: We conducted a cross sectional study of adults (age ≥ 18) newly diagnosed with iNHL at a single academic center. We enrolled consecutive patients who were diagnosed ≤ 3 months prior to study enrollment. At baseline, we collected patient reported outcomes to assess QOL (Functional Assessment of Cancer Therapy), psychological symptoms (Hospital Anxiety and Depression Scale), prognostic understanding (Prognostic Awareness Impact Scale), and coping (Brief COPE). We categorized coping as approach-oriented (active coping, use of emotional support, positive reframing, acceptance) and avoidant (behavioral disengagement, denial, and self-blame). We used median split to differentiate between low and high utilizers of approach or avoidant coping. Results: We enrolled 70.6% (48/68) of eligible patients newly diagnosed with iNHL (mean age 66.8 yrs; 39.6% chronic lymphocytic leukemia/ lymphoma; 33.3% follicular lymphoma). At baseline, nearly one-third (31.2%) experience clinically significant symptoms of anxiety and depression. 45.8% of patients identified prognostic uncertainty as the “the most stressful part of being a patient,” and 31.2% reported having “difficulty letting go of thoughts about their prognosis.” Notably, patients had significant misperceptions about their prognosis with incurable iNHL, as 47.9% reporting that a cure was at least ‘somewhat’ likely. Patients with iNHL most often used acceptance (56.3%), denial (47.9%), and emotional support (47.9%) as coping strategies. Patients who were high utilizers of multiple approach-oriented coping strategies experienced fewer anxiety (B = -2.66, p = 0.01) and depression (B = -1.73, p = 0.02) symptoms and improved QOL (B = 9.43, p = 0.001). Patients who highly utilized any avoidant-oriented coping strategies experienced increased anxiety symptoms (B = 2.16, p = 0.05), but no difference in depression symptoms or QOL. Conclusions: Patients with iNHL report immense prognostic uncertainty and psychological distress. Use of multiple approach oriented coping strategies was associated with decreased psychological distress and improved QOL. Interventions to address prognostic uncertainty and to promote approach oriented coping in patients with iNHL are sorely needed and have the potential to ameliorate psychological distress and improve QOL in this vulnerable population.